bluuebunny/crossref_metadata_2025_split huggingface dataset:
GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation in CLN1 disease
Authors: Tong Jia , Gao Jingjing , Qi Yawei , Gao Ziyan , Liu Yang , Wang Qianqian , Yuan Tiangang , Ren Minglong , Yang Guixia , Li Zhaoyue , Li Jin , Sun Hongyuan , Zhao Xing , Li Junmei , Leung Yeung-Yeung , Mu Yonghui , Xu Jiamin , Lu Chengbiao , Peng Shiyong , Ge Lihao 
Published: March 2024

SummaryCLN1 disease, also called infantile neuronal ceroid lipofuscinosis, is a fatal neurodegenerative disease caused by mutations in the CLN1 gene encoding palmitoyl protein thioesterase 1 (PPT1). To identify depalmitoylation substrate of PPT1 is crucial to understand CLN1 disease. In this study, we found that PPT1 depalmitoylates GABAAR α1 subunit at Cystein-260, while binding to Cystein-165 and −179. Mutations of PPT1 or its GABAAR α1 subunit binding site result in enhanced inhibitory synaptic transmission, strengthened and oscillation but disrupted phase coupling in CA1 region and impaired learning and memory in 1- to 2-months-old PPT1-deficient andGabra1em1mice. Our study highlights the critical role of PPT1 in maintaining GABAAR palmitoylation homeostasis and reveals a previously unknown molecular pathway in PPT1 induced diseases.
Origins of noise in both improving and degrading decision making
Authors: Shen Bo , Nguyen Duc , Wilson Jailyn , Glimcher Paul W. , Louie Kenway 
Published: March 2024

AbstractNoise is a fundamental problem for information processing in neural systems. In decision-making, noise is thought to cause stochastic errors in choice. However, little is known about how noise arising from different sources may contribute differently to value coding and choice behaviors. Here, we examine how noise arising early versus late in the decision process differentially impacts context-dependent choice behavior. We find in model simulations that under early noise, contextual information enhances choice accuracy, while under late noise, context degrades choice accuracy. Furthermore, we verify these opposing predictions in experimental human choice behavior. Manipulating early and late noise – by inducing uncertainty in option values and controlling time pressure – produces dissociable positive and negative context effects. These findings reconcile controversial experimental findings in the literature, suggesting a unified mechanism for context-dependent choice. More broadly, these findings highlight how different sources of noise can interact with neural computations to differentially modulate behavior.SignificanceThe current study addresses the role of noise origin in decision-making, reconciling controversies around how decision-making is impacted by context. We demonstrate that different types of noise – either arising early during evaluation or late during option comparison - leads to distinct results: with early noise, context enhances choice accuracy, while with late noise, context impairs it. Understanding these dynamics offers potential strategies for improving decision-making in noisy environments and refining existing neural computation models. Overall, our findings advance our understanding of how neural systems handle noise in essential cognitive tasks, suggest a beneficial role for contextual modulation under certain conditions, and highlight the profound implications of noise structure in decision-making.
Human visual performance for identifying letters affected by physiologically-inspired scrambling
Authors: Zhu Xingqi R , Hess Robert F , Baldwin Alex S 
Published: March 2024

AbstractIn human vision, the retinal input is transformed into internal representations through a series of stages. In earlier stages, the signals from a particular visual field locus are passed in parallel from one visual processing area to the next. The connections at each stage may therefore introduce “error”, where incorrect or convergent projections result in a loss of spatial precision. Psychophysical and physiological studies have implicated spatial scrambling of this sort as a cause of the visual deficits in amblyopia. Several methods to measure scrambling (both in amblyopia and in healthy vision) have been developed in recent decades. In this work, we introduce a new approach. We consider two stages of visual processing where scrambling may occur: either at the input to or the output from the simple cell stage in V1. We refer to these as “subcortical” and “cortical” scrambling respectively. We investigated the impact of these two types of scrambling on a letter identification task. A physiologically-inspired decomposition and resynthesis algorithm was used to generate letter stimuli that simulate scrambling at each of these two stages. To establish a performance benchmark, we trained separate Convolutional Neural Networks (CNNs) to perform the task with each scrambling type. Comparing CNN performance against that of eight humans with normal healthy vision, we found humans exhibited greater resilience to subcortical scrambling compared to cortical scrambling. We further investigated performance by comparing confusion matrices. Compared to a simple template matching model, we found the human strategy to be more consistent with our CNNs. We conclude: i) the human resilience for subcortical scrambling suggests this may be the stage at which a greater degree of scrambling is introduced in the visual hierarchy, and ii) humans employ flexible strategies for identifying scrambled stimuli, more sophisticated than a simple template match to the expected target.
Deciphering the Timing and Impact of Life-extending Interventions: Temporal Efficacy Profiler Distinguishes Early, Midlife, and Senescence Phase Efficacies
Authors: Jiang Nisi , Cheng Catherine J. , Liu Qianqian , Strong Randy , Gelfond Jonathan , Nelson James F. 
Published: March 2024

AbstractEvidence that life-extending interventions are not uniformly effective across the lifespan calls for an analytic tool that can estimate age-specific treatment effects on mortality hazards. Here we report such a tool, applying it to mouse data from 42 compounds tested in the NIA Interventions Testing Program. This tool identified agents that either reduced (22) or increased (15) mortality hazards or did both (2) in at least one sex, most with marked variation in the duration of efficacy and magnitude of effect size. Only 8 reduced mortality hazards after 90% mortality, when the burden of senescence is the greatest. Sex differences were common. This new analytic tool complements the commonly used log-rank test. It detects more potential life-extending candidates (22 versus 10) and indicates when during the life course they are effective. It also uncovers adverse effects.
Robust characterization of forest structure from airborne laser scanning – a systematic assessment and sample workflow for ecologists
Authors: Fischer Fabian Jörg , Jackson Toby , Vincent Grégoire , Jucker Tommaso 
Published: March 2024

AbstractForests display tremendous structural diversity, shaping carbon cycling, microclimates, and terrestrial habitats. One of the most common tools for forest structure assessments are canopy height models (CHMs): maps of canopy height obtained at high resolution and large scale from airborne laser scanning (ALS). CHMs can be computed in many ways, but little is known about the robustness of different CHM algorithms and how they affect ecological analyses.Here, we used high-quality ALS data from nine sites in Australia, ranging from semi-arid shrublands to 90-m tall Mountain Ash canopies, to comprehensively assess CHM algorithms. This included testing their sensitivity to point cloud degradation and quantifying the propagation of errors to derived metrics of canopy structure.We found that CHM algorithms varied widely both in their height predictions (differences up to 10 m, or 60% of canopy height) and in their sensitivity to point cloud characteristics (biases of up to ∼5 m or 40% of canopy height). Impacts of point cloud properties on CHM-derived metrics varied, from robust inference for height percentiles, to considerable errors in aboveground biomass estimates (∼50 Mg ha−1, or 10% of total), and high volatility in metrics that quantify spatial associations in canopies (e.g., gaps or spatial autocorrelation). In some cases, biases exceeded ecological variation across sites by a factor of 2. However, we also found that two CHM algorithms – a variation on a “spikefree” algorithm that adapts to local pulse densities and a simple Delaunay triangulation of first returns – allowed for robust canopy characterization and should thus create a secure foundation for ecological comparisons in space and time.Canopy height models are a widely used tool in ecology, but their derivation is not trivial. Our study provides a best-practice guideline and a sample workflow to create robust CHMs and minimize biases and uncertainty in downstream analyses. In doing so we pave the way for global-scale comparisons of forest structural complexity from airborne laser scanning.
Design and Assembly of a Cargo-agnostic Hollow Two-lidded DNA Origami Box for Drug Delivery
Authors: Koep Abigail , Masud Nabila , Van’t Hul Jaylee , Stanley Carson , Nilsen-Hamilton Marit , Sarkar Anwesha , Schneider Ian C. 
Published: March 2024

AbstractDNA origami, a method of folding DNA into precise nanostructures, has emerged as a powerful tool to design complex nanoscale shapes with movable parts. DNA origami has great potential as a drug delivery system that can encapsulate and protect a range of cargos spanning small molecules through large proteins, while remaining stable in a variety ofex vivoprocessing conditions andin vivoenvironments. DNA origami has been utilized for drug delivery applications, but the vast majority of these structures have been flexible, flat 2D or solid 3D nanostructures. There is a crucial need for a hollow and completely enclosed design capable of holding any type of cargo. In this paper, we present the design and assembly of a hollow DNA origami “box” with two actuatable lids. We characterize isothermal conditions for structural assembly in minutes that eliminates the need for a thermocycler. The stability of these structures is outstanding, remaining stable at body temperature and low pH for weeks and in the presence of solvents and biological fluids over several days. We demonstrate that passive loading of small molecules is charge dependent. We also outline an approach to design staple extensions pointing into the cavity or outside of the hollow DNA origami, allowing for either active loading of protein or the potential for decoration with passivating or targeting molecules. Future work includes fitting this hollow DNA origami structure with alternative lid opening mechanisms to release a variety of different cargos in response to environmental cues.Graphical Abstract
ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration
Authors: Pourshafie Naemeh , Xu Hong , Yang Kechun , Donahue Greg , Lei Xue , Zhang Shuo , Shcherbakova Oksana , Hogan Connor , Gilbert Michael , Hoxha Kevt’her , Chaboub Lesley , Lee Virginia , Adams Peter , Dani John A. , Bonini Nancy , Berger Shelley 
Published: March 2024

ABSTRACTEpigenetic mechanisms, including histone acetylation, are pivotal for learning and memory, with a role in neuronal function in Alzheimer’s disease and Related Dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme that generates acetyl-CoA, is central to histone acetylation and gene regulation, particularly in neurons, due to their unique metabolic demands and postmitotic state. ACSS2 can be recruited to the nucleus and chromatin, locally supplying acetyl-CoA to directly fuel histone acetyltransferase enzymes and key neuronal gene expression. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases. Previously we showed that systemic ACSS2 deletion in mice, although largely normal in physiology, is greatly impaired in memory. Here we investigated whether increasing ACSS2 levels could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology and the P301S transgenic mouse model for tau-induced memory decline. Our results show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Expanding upon these findings, we reveal that increasing histone acetylation through ACSS2 upregulation improves age-associated memory decline. These findings indicate that increasing ACSS2 is highly effective in countering age- and tau-induced transcriptome changes, preserving elevated levels of synaptic genes, and safeguarding synaptic integrity. We thus highlight ACSS2 as a key player in the epigenetic regulation of cognitive aging and ADRD, providing a foundation for targeted therapeutics to enhance brain resilience and function.SummaryACSS2 upregulation protects neurons from disease and age-related decline by enhancing synaptic and longevity gene expression.
Vitamin C preventsS. aureusinfections of endothelial cells through its interaction with specific residues in the active site of gC1qR/p33 involved in direct entry, notably SER230, ASN345, ILE348, TYR224, ASN346, SER347, and GLU438, and its potential inhibitory effects on FnBPs, α5β1, and Protein A molecules
Authors: Miliani Maroua , Hadjidj Zeyneb , Bensefia Zakariya , Dahou Sara , Ammouche Nasreddine , Hamdoun Imane , Benammar Hadjer , Benammar Sarah , Aribi Mourad 
Published: March 2024

AbstractStaphylococcus aureus(S. aureus), often perceived as an extracellular pathogenic agent, exhibits a remarkable ability to penetrate host cells, including endothelial, epithelial, and osteoblastic cells, significantly contributing to the pathogenesis of infections. A significant pathway for this invasion appears to involve the bacterium’s binding to the α5β1 integrinviaa fibronectin bridge, followed by phagocytosis. Additionally,S. aureuspresents staphylococcal protein A, a cell wall protein that binds to the Fc and Fab regions of immunoglobulins, playing a crucial role in virulence and immune evasion, and can also bind directly to the gC1qR receptor on endothelial cells. Furthermore, vitamin C is recognized for its antimicrobial and immunomodulatory properties, offering potential for reducing the risk of infection. Considering the aforementioned elements, our study focused on exploring the potential effects of vitamin C on the interactions betweenS. aureusand endothelial cells. Thus, we particularly examined two aspects: on the one hand, interactions involving fibronectin-binding proteins (FnBPs) proteins and human α5β1 integrin, and on the other hand, the interaction between vitamin C and the direct entry receptor (the globular heads of complement component 1q receptor [gC1qR/p33], also known as hyaluronic acid binding protein 1 [HABP1]). To achieve this, we utilized molecular modeling assays, primarily relying on molecular docking.
A shared genetic basis for sexually antagonistic male and female adaptations in the toothed water strider
Authors: Pruvôt Claudia , Armisen David , Roux Pascale , Arnqvist Göran , Rowe Locke , Husby Arild , Khila Abderrahman 
Published: March 2024

AbstractSexual conflict can drive the divergence of male and female phenotypes and several cross-species comparative analyses have documented patterns of correlated evolution of sex-specific traits that promote the evolutionary interests of the sexes. However, male-female coevolution can be highly dynamic. Moreover, if male and female traits do not have an entirely distinct genetic basis, this can have profound effects on their coevolutionary dynamics. Here, we use water striders, a well-studied model system for sexually antagonistic coevolution, and ask whether sex-specific phenotypic adaptations covary across populations and whether they share a common developmental genetic basis. Using comparative analyses both at the population and species levels, we document an association between a derived male mate-grasping trait and a likely female anti-grasping counteradaptation in the toothed water striderGerris odontogaster. Interestingly, in one population where males did not express their derived grasping trait, females had also regained the ancestral morphology. We then used experimental manipulation of gene expression, and show that these male and female traits are both linked to a common developmental genetic program containing Hox and sex determination genes, despite the fact that they are different structures on different segments. Our work thus suggests that the pleiotropic nature of developmental genetic programs can blur the distinction between inter- and intralocus genetic conflict.
Bayesian inference of phylogenetic distances: revisiting the eigenvalue approach
Authors: Penn Matthew J. , Scheidwasser Neil , Donnelly Christl A. , Duchêne David A. , Bhatt Samir 
Published: March 2024

AbstractUsing genetic data to infer evolutionary distances between molecular sequence pairs based on a Markov substitution model is a common procedure in phylogenetics, in particular for selecting a good starting tree to improve upon. Many evolutionary patterns can be accurately modelled using substitution models that are available in closed form, including the popular general time reversible model (GTR) for DNA data. For more unusual biological phenomena such as variations in lineage-specific evolutionary rates over time (heterotachy), more complex approaches uch as the GTR with rate variation (GTR+G) are required, but do not admit analytical solutions and do not automatically allow for likelihood calculations crucial for Bayesian analysis. In this paper, we derive a hybrid approach between these two methods, incorporatingG(α, α)-distributed rate variation and heterotachy into a hierarchical Bayesian GTR-style framework. Our approach is differentiable and amenable to both stochastic gradient descent for optimisation and Hamiltonian Markov chain Monte Carlo for Bayesian inference. We show the utility of our approach by studying hypotheses regarding the origins of the eukaryotic cell within the context of a universal tree of life and find evidence for a two-domain theory.
Evidence for flexible motor costs in vertical arm movements: reduced gravity-related effort minimization under high accuracy constraints
Authors: Poirier Gabriel , De Filippis Damien , Sirandre Cyril , Papaxanthis Charalambos , Gaveau Jeremie 
Published: March 2024

AbstractThe central nervous system (CNS) is thought to use motor strategies that minimize several criteria, such as end-point variability or effort, to plan optimal motor patterns. In the case of vertical arm movements, a large body of literature demonstrated that the brain uses a motor strategy that takes advantage of the mechanical effects of gravity to minimize muscle effort. Results from other studies suggested that the relative importance of each criterion may vary according to the task’s constraints. For example, it could be hypothesized that reduced end-point variability driven by high accuracy demands is detrimental to effort minimization. The present study probes this specific hypothesis using the framework of gravity-related effort minimization. We asked twenty young healthy participants to perform vertical arm reaching movements towards targets whose size varied across conditions. We recorded the arm kinematics and electromyographic activities of the anterior deltoid to study two well-known motor signatures of the gravity-related optimization process; i.e., directional asymmetries on velocity profiles and negative epochs on phasic muscular activities. The results showed that both indices were reduced as target size decreased, demonstrating that the gravity-related optimization process was reduced under high accuracy constraints. This phenomenon is consistent with the use of a trade-off strategy between effort and end-point variability. More generally, it suggests that the CNS is able to appropriately modulate the relative importance of varied motor costs when facing varying task demands.
Genetic diversity affects ecosystem functions across trophic levels as much as species diversity, but in an opposite direction
Authors: Fargeot Laura , Poesy Camille , Lefort Maxim , Prunier Jérôme G. , Krick Madoka , Verdonck Rik , Veyssière Charlotte , Richard Murielle , Legrand Delphine , Loot Géraldine , Blanchet Simon 
Published: March 2024

ABSTRACTUnderstanding the relationships between biodiversity and ecosystem functioning stands as a cornerstone in ecological research. Extensive evidence now underscores the profound impact of species loss on the stability and dynamics of ecosystem functions. However, it remains unclear whether the loss of genetic diversity within key species yield similar consequences. Here, we delve into the intricate relationship between species diversity, genetic diversity, and ecosystem functions across three trophic levels —primary producers, primary consumers, and secondary consumers— in natural aquatic ecosystems. Our investigation involves estimating species diversity and genome-wide diversity -gauged within three pivotal species-within each trophic level, evaluating seven key ecosystem functions, and analyzing the magnitude of the relationships between biodiversity and ecosystem functions (BEFs). We found that, overall, the absolute effect size of genetic diversity on ecosystem functions mirrors that of species diversity in natural ecosystems. We nonetheless unveil a striking dichotomy: while genetic diversity was positively correlated with various ecosystem functions, species diversity displays a negative correlation with these functions. These intriguing antagonist effects of species and genetic diversity persists across the three trophic levels (underscoring its systemic nature), but were apparent only when BEFs were assessed within trophic levels rather than across them. This study reveals the complexity of predicting the consequences of genetic and species diversity loss under natural conditions, and emphasizes the need for further mechanistic models integrating these two facets of biodiversity.