bluuebunny/crossref_metadata_2025_split huggingface dataset:
Meta-Reinforcement Learning reconciles surprise, value and control in the anterior cingulate cortex
Authors: Vriens Tim , Vassena Eliana , Pezzulo Giovanni , Baldassarre Gianluca , Silvetti Massimo 
Published: May 2024

AbstractThe role of the dorsal anterior cingulate cortex (dACC) in cognition is a frequently studied yet highly debated topic in neuroscience. Most authors agree that the dACC is involved in either cognitive control (e.g. voluntary inhibition of automatic responses) or monitoring (e.g. comparing expectations with outcomes, detecting errors, tracking surprise). A consensus on which theoretical perspective best explains dACC contribution to behaviour is still lacking. In a recent neuroimaging study, the experimental predictions of two prominent models formalizing the cognitive control hypothesis (Expected Value of Control, EVC) and the monitoring hypothesis (Predicted Response Outcome, PRO) have been tested using a behavioural task involving both monitoring and cognitive control mechanisms. The results indicated that of the two tested models, only the PRO model effectively predicted the dACC activity, indicating surprise tracking for performance monitoring as the key sole underlying mechanism, even when cognitive control was required by the task at hand. These findings challenged the long-standing and established cognitive control hypothesis of dACC function and opened a theory crisis: the proposed surprise-monitoring hypothesis indeed cannot account for a wide array of previous experimental findings evidencing dACC activation in tasks requiring cognitive controlwithoutinvolving monitoring or surprise. Here we propose a novel hypothesis on dACC function that integrates both the monitoring and the cognitive control perspective in a unifying coherent framework, based on meta-Reinforcement Learning. Our model, the Reinforcement Meta Learner (RML), optimizes cognitive control - as in control models like EVC-by meta-learning based on tracking surprise - as in monitoring models like PRO. We tested RML experimental predictions with the same behavioural task used to compare the PRO and EVC models, and showed that RML predictions on dACC activity matched PRO predictions and outperformed EVC predictions. However, crucially, the RML simultaneously accounts for both cognitive control and monitoring functions, resolving the theoretical impasse about dACC function within an integrative framework. In sum, our results suggest that dACC function can be framed as a meta-learning optimiser of cognitive control, providing an integrative perspective on its roles in cognitive control, surprise tracking, and performance monitoring.
Abscisic Acid rescues behavior in adult female mice in Attention Deficit Disorder with Hyperactivity model of dopamine depletion by regulating microglia and vesicular GABA transporter
Authors: Meseguer-Beltrán Maria , Sánchez-Sarasúa Sandra , Kerekes Nóra , Landry Marc , Real-López Matías , Sánchez-Pérez Ana María 
Published: May 2024

AbstractBackgroundAttention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome influenced by both genetic and environmental factors. While genetic studies have highlighted catecholamine dysfunction, emerging epidemiological evidence suggest neuroinflammation as a significant trigger. However, understanding the relative contributions of these alterations to ADHD symptomatology remains elusive.MethodThis study employed 93 female Swiss mice of the ADHD dopamine deficit model. Dopaminergic lesions were induced via 6-hydroxidopamine (6-OHDA) injection on postnatal day 5. The impact of these lesions during development was examined by comparing young and adult mice (at postnatal day 21 and 90, respectively). We sought to mitigate adult symptoms through abscisic acid (ABA) administration during two-months. Postmortem analyses encompassed the evaluation of neuroinflammation (microglia morphology, NLRP3 inflammasome activation, cytokine expression) and excitatory/inhibitory (E/I) ratio in specific brain regions.ResultsNeonatal dopaminergic lesions elicited hyperactivity, impulsivity, hypersensitivity increased social interaction in both one-month and three-month females and induced impaired memory in three-month mice. ABA exposure significantly ameliorated hyperactivity, impulsivity, anxiety, hypersensitivity, and social interaction alterations, but not cognitive impairment. In the anterior cingulate cortex (ACC) of one-month mice dopamine-deficit elevated IL-1β and TNFα expression and reduced Arg1 mRNA levels, along with E/I imbalance. ABA intervention restored microglia morphology, IL-1β, Arg1 expression and enhanced vGAT levels.ConclusionsThis study strongly suggest that dopamine deficit induced alteration of microglia and E/I ratio underling distinct ADHD symptoms. Reinstating healthy microglia by anti-inflammatory agents in specific areas emerges as a promising strategy for managing ADHD.
High-throughput optimisation of protein secretion in yeast via an engineered biosensor
Authors: Williams Alexandra , Luo Runpeng , Smith Oliver B. , Murphy Lydia , Schwessinger Benjamin , Brock Joseph 
Published: May 2024

SummarySecretion of high value proteins and enzymes is fundamental to the synthetic biology economy; allowing continuous fermentation during production and protein purification without cell lysis. Most eukaryotic protein secretion is encoded by an N-terminal signal peptide; however, the strong impact of signal peptide sequence variation on the secretion efficiency of a given protein is not well defined. Despite high natural signal peptide sequence diversity, most recombinant protein secretion systems employ only a few well characterised signal peptides. Additionally, the selection of promoters and terminators can significantly affect secretion efficiency, yet screening numerous genetic constructs for optimal sequences remains inefficient. Here, we have adapted a yeast G-protein coupled receptor biosensor, to measure the concentration of a peptide tag that is co-secreted with any protein of interest. Protein secretion efficiency can thus be quantified via the induction of a fluorescent reporter that is upregulated downstream of receptor activation. This enables high-throughput screening of over 6000 combinations of promoters, signal peptides and terminators, assembled using one-pot Combinatorial Golden Gate cloning. We demonstrate this biosensor can quickly identify best combinations for secretion and quantify secretion levels.Graphical Abstract
Investigating tissue microstructure using steady-state diffusion MRI
Authors: Tendler Benjamin C. 
Published: May 2024

AbstractDiffusion MRI is a leading method to non-invasively characterise brain tissue microstructure across multiple domains and scales. Diffusion-weighted steady-state free precession (DW-SSFP) is an established imaging sequence for post-mortem MRI, addressing the challenging imaging environment of fixed tissue with short T2and low diffusivities. However, a current limitation of DW-SSFP is signal interpretation: it is not clear what diffusion ‘regime’ the sequence probes and therefore its potential to characterise tissue microstructure. Building on a model of Extended Phase Graphs (EPG), I establish two alternative representations of the DW-SSFP signal in terms of (1) conventional b-values (time-independentdiffusion) and (2) encoding power-spectra (time-dependentdiffusion). The proposed representations provide insights into how different parameter regimes and gradient waveforms impact the diffusion properties of DW-SSFP. Using these representations, I introduce an approach to incorporate existing diffusion models into DW-SSFP without the requirement of extensive derivations. Investigations incorporating free-diffusion and tissue-relevant microscopic restrictions (cylinder of varying radius) give excellent agreement to complementary analytical models and Monte Carlo simulations. Experimentally, the time-independentrepresentation is used to derive Tensor and proof of principle NODDI estimates in a whole human post-mortem brain. A final SNR-efficiency investigation demonstrates the theoretical potential of DW-SSFP for ultra-high field microstructural imaging.
Programming CRISPRi-dCas9 to control the lifecycle of bacteriophage T7
Authors: Bergmiller Tobias 
Published: May 2024

AbstractCRISPR interference (CRISPRi) based on catalytically dead Cas9 nuclease ofStreptococcus pyogenesis a programmable and highly flexible tool to interrogate gene function and essentiality in bacteria due to its ability to block transcription elongation at nearly any desired DNA target. Here, I assess how CRISPRi-dCas9 can be programmed to control the life cycle and infectivity ofEscherichia colibacteriophage T7, a highly virulent and obligatory lytic phage, by blocking critical host-dependent promoters that are required for host cell entry and life cycle execution. Using fluorescent reporters demonstrates that the efficacy of CRISPRi-dCas9 towardsE. coliRNAP promoters depends on target promoter strength, and that the phage’s own T7 RNAP can be downregulated very efficiently. Effects on the time to lysis were partially dictated by the chronological order of phage DNA and dCas9 target appearance in the cell, suggesting an accessory role ofE. coliRNAP during the early stages of T7 genome ejection. The stringency of the CRISPRi-dCas9 approach was greatly improved when using multiplex sgRNAs to target multiple phage regions simultaneously, resulting in a 25% increase in the time to lysis and up to 8-fold reduction in plaque size. Overall, this work expands CRISPRi-dCas9 as a flexible tool to non-invasively manipulate and probe the lifecycle and infectivity of otherwise native T7 phage.
AARS Online: a collaborative database on the structure, function, and evolution of the aminoacyl-tRNA synthetases
Authors: Douglas Jordan , Cui Haissi , Perona John J. , Vargas-Rodriguez Oscar , Tyynismaa Henna , Alvarez Carreño Claudia , Ling Jiqiang , Ribas-de-Pouplana Lluís , Yang Xiang-Lei , Ibba Michael , Becker Hubert , Fischer Frédéric , Sissler Marie , Carter Charles W. , Wills Peter R. 
Published: May 2024

AbstractThe aminoacyl-tRNA synthetases (aaRS) are a large group of enzymes that implement the genetic code in all known biological systems. They attach amino acids to their cognate tRNAs, moonlight in various non-translational activities, and are linked to many genetic disorders. The aaRS have a subtle ontology characterized by structural and functional idiosyncrasies that vary from organism to organism, and protein to protein. Across the tree of life, the twenty-two coded amino acids are handled by sixteen evolutionary Families of Class I aaRS and twenty-one Families of Class II aaRS. We introduce AARS Online, an interactive Wikipedia-like tool curated by an international consortium of field experts. This platform systematizes existing knowledge about the aaRS by showcasing a taxonomically diverse selection of aaRS sequences and structures. Through its graphical user interface, AARS Online facilitates a seamless exploration between protein sequence and structure, providing a friendly introduction to the material for non-experts and a useful resource for experts. Curated multiple sequence alignments can be extracted for downstream analyses. Accessible atwww.aars.online, AARS Online is a free resource to delve into the world of the aaRS.
Reducing neuronal nitric oxide synthase (nNOS) expression in the ventromedial hypothalamus (VMH) increases body weight and blood glucose levels while decreasing physical activity in female mice
Authors: Hirschberg Pamela R. , Siegel Dashiel M. , Teegala Suraj , Rahbe Munir , Sarkar Pallabi , Routh Vanessa H. 
Published: May 2024

ABSTRACTGlucose-inhibited (GI) neurons of the ventromedial hypothalamus (VMH) depend on neuronal nitric oxide synthase (nNOS) and AMP-activated protein kinase (AMPK) for activation in low glucose. The Lopez laboratory has shown that the effects of estrogen on brown fat thermogenesis and white fat browning require inhibition of VMH AMPK. This effect of estrogen was mediated by downstream lateral hypothalamus (LH) orexin neurons1,2. We previously showed that estrogen inhibits activation of GI neurons in low glucose by inhibiting AMPK3. Thus, we hypothesized that VMH AMPK- and nNOS-dependent GI neurons project to and inhibit orexin neurons. Estrogen inhibition of AMPK in GI neurons would then disinhibit orexin neurons and stimulate brown fat thermogenesis and white fat browning, leading to decreased body weight. To test this hypothesis, we reduced VMH nNOS expression using nNOS shRNA in female mice and measured body weight, adiposity, body temperature, white and brown fat uncoupling protein (UCP1; an index of thermogenesis and browning), locomotor activity, and blood glucose levels. Surprisingly, we saw no effect of reduced VMH nNOS expression on body temperature or UCP1. Instead, body weight and adiposity increased by 30% over 2 weeks post injection of nNOS shRNA. This was associated with increased blood glucose levels and decreased locomotor activity. We also found that VMH nNOS-GI neurons project to the LH. However, stimulation of VMH-LH projections increased excitatory glutamate input onto orexin neurons. Thus, our data do not support our original hypothesis. Excitation of orexin neurons has previously been shown to increase physical activity, leading to decreased blood glucose and body weight4. We now hypothesize that VMH nNOS-GI neurons play a role in this latter function of orexin neurons.
Synchronization of the prefrontal cortex with the hippocampus and posterior parietal cortex is navigation strategy-dependent during spatial learning
Authors: García F. , Torres M-J. , Chacana-Véliz L. , Espinosa N. , El-Deredy W. , Fuentealba P. , Negrón-Oyarzo I. 
Published: May 2024

1.ABSTRACTDuring goal-directed spatial learning, subjects progressively change their navigation strategies to increase their navigation efficiency, an operation supported by the medial prefrontal cortex (mPFC). However, how the mPFC may integrate relevant information in a wider memory networks involving the hippocampus (HPC) and the posterior parietal cortex (PPC) is poorly understood. We recorded local-field potential and neuronal firing simultaneously from the mPFC, HPC and PPC in mice subjected to spatial memory acquisition in the Barnes maze. During navigation trials, animals demonstrated two consecutive behavioral stages: searching and exploration. Throughout training, mice gradually switched from less efficient (non-spatial) to more efficient (spatial) goal-oriented strategies exclusively during the searching stage. 4-Hz and theta (6-12 Hz) oscillations were detected during spatial navigation in the three recorded areas associated with episodes of immobility and locomotion, respectively. The entrainment of prefrontal gamma oscillations (60-100 Hz) by hippocampal and parietal 4-Hz and theta oscillations, as well as the incidence of prefrontal gamma, was higher when mice implemented spatial strategies during the searching stage. Interestingly, 4-Hz and theta from HPC and PPC also synchronized the spike-timing of prefrontal neurons, which was maximum during spatial strategies in the searching stage. Finally, neurons recorded in the mPFC increased their task stage firing selectivity when they used spatial strategy. Altogether, these results provide evidence for the neural mechanisms underlying the prefrontal large-scale coordination with distributed neural networks during spatial learning.
Rapid modulation of striatal cholinergic interneurons and dopamine release by satellite astrocytes
Authors: Stedehouder Jeffrey , Roberts Bradley M. , Raina Shinil , Bossi Simon , Liu Alan King Lun , Doig Natalie M. , McGerty Kevin , Magill Peter J. , Parkkinen Laura , Cragg Stephanie J. 
Published: May 2024

SUMMARYAstrocytes are increasingly thought to have underestimated and important roles in modulating neuronal circuits. Astrocytes in striatum can regulate dopamine transmission by governing the extracellular tone of axonal neuromodulators, including GABA and adenosine. However, here we reveal that striatal astrocytes occupy a cell type-specific anatomical and functional relationship with cholinergic interneurons (ChIs), through which they rapidly excite ChIs and govern dopamine release via nicotinic acetylcholine receptors on subsecond timescales. We identify that ChI somata are in unexpectedly close proximity to astrocyte somata, in mouse and human, forming a “soma-to-soma” satellite-like configuration not typically observed for other striatal neurons. Transient depolarization of astrocytes in mouse striatum reversibly regulated ChI excitability by decreasing extracellular calcium. These findings reveal a privileged satellite astrocyte-interneuron interaction for striatal ChIs operating on subsecond timescales via regulation of extracellular calcium dynamics to shape downstream striatal circuit activity and dopamine signaling.
An AI-Driven Framework for Discovery of BACE1 Inhibitors for Alzheimer’s Disease
Authors: Xie Evan , Hasegawa Karin , Kementzidis Georgios , Papadopoulos Evangelos , Aktas Bertal Huseyin , Deng Yuefan 
Published: May 2024

AbstractAlzheimer’s Disease (AD) is a progressive neurodegenerative disorder that affects over 51 million individuals globally. Theβ-secretase (BACE1) enzyme is responsible for the production of amyloid beta (Aβ) plaques in the brain. The accumulation of Aβplaques leads to neuronal death and the impairment of cognitive abilities, both of which are fundamental symptoms of AD. Thus, BACE1 has emerged as a promising therapeutic target for AD. Previous BACE1 inhibitors have faced various issues related to molecular size and blood-brain barrier permeability, preventing any of them from maturing into FDA-approved AD drugs. In this work, a generative AI framework is developed as the first AI application to thede novogeneration of BACE1 inhibitors. Through a simple, robust, and accurate molecular representation, a Wasserstein Generative Adversarial Network with Gradient Penalty (WGAN-GP), and a Genetic Algorithm (GA), the framework generates and optimizes over 1,000,000 candidate inhibitors that improve upon the bioactive and pharmacological properties of current BACE1 inhibitors. Then, the molecular docking simulation models the candidate inhibitors and identifies 14 candidate drugs that exhibit stronger binding interactions to the BACE1 active site than previous candidate BACE1 drugs from clinical trials. Overall, the framework successfully discovers BACE1 inhibitors and candidate AD drugs, accelerating the developmental process for a novel AD treatment.
Trifunctional fatty acid derivatives demonstrate the impact of diazirine placement
Authors: Farley Scotland E , Hashimoto Ryu , Evangelista Judah , Stein Frank , Haberkant Per , Kikuchi Kazuya , Tafesse Fikadu G. , Schultz Carsten 
Published: May 2024

ABSTRACTFunctionalized lipid probes are a critical new tool to interrogate the function of individual lipid species, but the structural parameters that constrain their utility have not been thoroughly described. Here, we synthesize three palmitic acid derivatives with a diazirine at different positions on the acyl chain and examine their metabolism, subcellular localization, and protein interactions. We demonstrate that while they produce very similar metabolites and subcellular distributions, probes with the diazirine at either end pulldown distinct subsets of proteins after photo-crosslinking. This highlights the importance of thoughtful diazirine placement when developing probes based on biological molecules.
Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network
Authors: Matera A. Gregory , Steiner Rebecca E. , Mills C. Alison , Herring Laura E. , Garcia Eric L. 
Published: May 2024

AbstractMolecular chaperones and co-chaperones are highly conserved cellular components that perform variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an RNP assembly chaperone and serves as a paradigm for studying how specific small nuclear (sn)RNAs are identified and paired with their client substrate proteins. SMN protein is the eponymous component of a large complex required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs) and localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN forms the oligomeric core of this complex, and missense mutations in its YG box self-interaction domain are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood. Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners.Here, we carried out affinity purification mass spectrometry (AP-MS) of SMN using stable fly lines exclusively expressing either wildtype or SMA-causing missense alleles. Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially interacted with SMA-causing alleles of SMN. Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse andDrosophilaALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.
A left-lateralized dorsolateral prefrontal network for naming
Authors: Yu Leyao , Dugan Patricia , Doyle Werner , Devinsky Orrin , Friedman Daniel , Flinker Adeen 
Published: May 2024

AbstractThe ability to connect the form and meaning of a concept, known as word retrieval, is fundamental to human communication. While various input modalities could lead to identical word retrieval, the exact neural dynamics supporting this convergence relevant to daily auditory discourse remain poorly understood. Here, we leveraged neurosurgical electrocorticographic (ECoG) recordings from 48 patients and dissociated two key language networks that highly overlap in time and space integral to word retrieval. Using unsupervised temporal clustering techniques, we found a semantic processing network located in the middle and inferior frontal gyri. This network was distinct from an articulatory planning network in the inferior frontal and precentral gyri, which was agnostic to input modalities. Functionally, we confirmed that the semantic processing network encodes word surprisal during sentence perception. Our findings characterize how humans integrate ongoing auditory semantic information over time, a critical linguistic function from passive comprehension to daily discourse.