bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneous and higher-order cortical connectivity undergirds efficient, robust and reliable neural codes
Authors: Egas Santander Daniela , Pokorny Christoph , Ecker András , Lazovskis Jānis , Santoro Matteo , Smith Jason P. , Hess Kathryn , Levi Ran , Reimann Michael W. 
Published: March 2024

AbstractSimplified models of neural networks have demonstrated the importance of establishing a reasonable tradeoff between memory capacity and fault-tolerance in cortical coding schemes. The intensity of the tradeoff is mediated by the level of neuronal variability. Indeed, increased redundancy in neuronal activity enhances the robustness of the code at the cost of the its efficiency. We hypothesized that the heterogeneous architecture of biological neural networks provides a substrate to regulate this tradeoff, thereby allowing different subpopulations of the same network to optimize for different objectives. To distinguish between subpopulations, we developed a metric based on the mathematical theory of simplicial complexes that captures the complexity of their connectivity, by contrasting its higher-order structure to a random control. To confirm the relevance of our metric we analyzed several openly available connectomes, revealing that they all exhibited wider distributions of simplicial complexity across subpopulations than relevant controls. Using a biologically detailed cortical model and an electron microscopic data set of cortical connectivity with co-registered functional data, we showed that subpopulations with low simplicial complexity exhibit efficient activity. Conversely, subpopulations of high simplicial complexity play a supporting role in boosting the reliability of the network as a whole, softening the robustness-efficiency tradeoff. Crucially, we found that both types of subpopulations can and do coexist within a single connectome in biological neuronal networks, due to the heterogeneity of their connectivity. Our work thus suggests an avenue for resolving seemingly paradoxical previous results that assume homogeneous connectivity.
Widespread innervation of motoneurons by spinal V3 neurons globally amplifies locomotor output in mice
Authors: Zhang Han , Deska-Gauthier Dylan , MacKay Colin S. , Hari Krishnapriya , Lucas-Osma Ana M. , Borowska-Fielding Joanna , Letawsky Reese L. , Akay Turgay , Fenrich Keith K. , Bennett David J. , Zhang Ying 
Published: March 2024

AbstractWhile considerable progress has been made in understanding the neuronal circuits that underlie the patterning of locomotor behaviours such as walking, less is known about the circuits that amplify motoneuron output to enable adaptable increases in muscle force across different locomotor intensities. Here, we demonstrate that an excitatory propriospinal neuron population (V3 neurons, Sim1+) forms a large part of the total excitatory interneuron input to motoneurons (∼20%) across all hindlimb muscles. Additionally, V3 neurons make extensive connections among themselves and with other excitatory premotor neurons (such as V2a neurons). These circuits allow local activation of V3 neurons at just one segment (via optogenetics) to rapidly depolarize and amplify locomotor-related motoneuron output at all lumbar segments in both the in vitro spinal cord and the awake adult mouse. Interestingly, despite similar innervation from V3 neurons to flexor and extensor motoneuron pools, functionally, V3 neurons exhibit a pronounced bias towards activating extensor muscles. Furthermore, the V3 neurons appear essential to extensor activity during locomotion because genetically silencing them leads to slower and weaker mice with a poor ability to increase force with locomotor intensity, without much change in the timing of locomotion. Overall, V3 neurons increase the excitability of motoneurons and premotor neurons, thereby serving as global command neurons that amplify the locomotion intensity.
HUHgle: An Interactive Substrate Design Tool for Covalent Protein-ssDNA Labeling Using HUH-tags
Authors: Smiley Adam T. , Babilonia-Díaz Natalia S. , Hughes Aspen J. , Lemmex Andrew C.D. , Anderson Michael J.M. , Tompkins Kassidy J. , Gordon Wendy R. 
Published: March 2024

AbstractHUH-tags have emerged as versatile fusion partners that mediate sequence specific protein-ssDNA bioconjugation through a simple and efficient reaction. Here we present HUHgle, a python-based interactive tool for the visualization, design, and optimization of substrates for HUH-tag mediated covalent labeling of proteins of interest with ssDNA substrates of interest. HUHgle streamlines design processes by integrating an intuitive plotting interface with a search function capable of predicting and displaying protein-ssDNA bioconjugate formation efficiency and specificity in proposed HUH-tag/ssDNA sequence combinations. Validation demonstrates that HUHgle accurately predicts product formation of HUH-tag mediated bioconjugation for single- and orthogonal-labeling reactions. In order to maximize the accessibility and utility of HUHgle, we have implemented it as a user-friendly Google Colab notebook which facilitates broad use of this tool, regardless of coding expertise.Graphical Abstract
Cell-type specialization of layer 5 excitatory neurons in tactile behavior
Authors: King Samson G. , Maire Phillip , Mergenthal Adam , Walker Stefanie , Hires Samuel Andrew 
Published: March 2024

AbstractLayer 5 is the canonical output layer of sensory cortex. The two most numerous neural constituents of Layer 5 are pyramidal tract (PT) and intratelencephalic (IT) neurons. These output cell classes combine diverse sets of inputs and project to distinct locations across the brain, suggesting differing roles in sensory information processing. Here, we investigated the representation of touch and whisker motion in these two cell types within primary somatosensory cortex (S1) using optogenetically targeted single unit electrophysiology during whisker-guided object localization. PT neurons (N = 32) had much higher spike rates than IT (N=26) during behavior. Individual members of both were modulated by, but average population firing rates were stable between quiet and whisking periods. PT neurons showed greater absolute spike rate changes, but less relative modulation than IT neurons to whisking kinematic features. Touch-excited PT (N = 18) and IT neurons (N = 8) rapidly adapted to active touch. Both populations encoded the azimuthal position of touched objects, with IT neurons more sharply tuned to position. However, position was more precisely decodable from PT population activity, due to greater evoked spikes per touch. A consequence of these characteristics is that PT neurons, with their higher firing rates, may be more effective participants in rate-based neural codes, while IT neurons, with their sharp modulation, may be more effective in timing or synchrony-based codes.
Redox-dependent synaptic clustering of gephyrin
Authors: Gehling Maria-Theresa , Liebsch Filip , Jacobs Lianne , Riemer Jan , Schwarz Günter 
Published: March 2024

ABSTRACTReactive oxygen species (ROS) play a central role in enhancing inhibitory signal transmission, thus extending their role beyond oxidative stress in disease and aging. However, the underlying molecular mechanisms mediating these functions have remained elusive. At inhibitory synapses, the scaffolding protein gephyrin clusters glycine and GABA type A receptors. Since gephyrin harbors multiple surface-exposed cysteines, we investigated the regulatory influence of ROS on gephyrin. We show that H2O2-induced oxidation of gephyrin cysteines triggered reversible, synaptic multimerization through disulfide bridge formation, which provided more receptor binding sites, lead to proteolytic protection and enhanced liquid-liquid phase separation. We identified mitochondria-derived ROS as a physiological source and observed oxidized gephyrin multimersin vivo,indicating that gephyrin can be regulated by the redox environment. Collectively, our findings suggest that cysteines in gephyrin modulate synaptic localization and clustering as regulatory redox-switches thereby establishing a link between neuronal and mitochondrial activity.
Nuclear compression-mediated DNA damage drives ATR-dependent Lamin expression and mouse ESC differentiation
Authors: Roy Tanusri , Ghosh Swetlana , Piplani Niyati , Sthanam Lakshmi Kavitha , Tiwary Niharika , Dhar Sayak , Konyak W. Chingmei Wangsa , Panigrahi Santosh Surendra , Singh Priya , Sowpati Divya Tej , Nair Sreelaja , Kumar Sushil , Shekar P. Chandra , Sen Shamik 
Published: March 2024

AbstractEmbryonic stem cells (ESCs) which are susceptible to DNA damage depend on a robust and highly efficient DNA damage response (DDR) mechanism for their survival. However, the implications of physical force-mediated DNA damage on ESC fate remains unclear. We show that stiffness-dependent spreading of mouse ESCs (mESCs) induces DNA damage through nuclear compression, with DNA damage causing differentiation through early induction of Lamin A/C expression. Interestingly, differentiation is associated with rescue of DNA damage and activation of the DDR factor ATR. While ATR is typically known to play roles in DDR pathway, its role during stiffness-mediated nuclear compression and mESC differentiation is unknown. Nuclear enrichment of activated ATR on stiff substrates and reduction of Lamin A/C expression upon ATR inhibition suggests that mESC differentiation is driven by nuclear compression-mediated DNA damage and involves ATR-dependent modulation of Lamin A/C.
Putaminal dopamine modulates movement motivation in Parkinson’s disease
Authors: Banwinkler Magdalena , Dzialas Verena , Rigoux Lionel , Asendorf Adrian L. , Theis Hendrik , Giehl Kathrin , Tittgemeyer Marc , Hoenig Merle C. , van Eimeren Thilo 
Published: March 2024

AbstractThe relative inability to produce effortful movements (akinesia) is the most specific motor sign of Parkinson’s disease. The motor motivation hypothesis suggests that akinesia may not reflect a deficiency in motor controlper se, but a deficiency in cost-benefit considerations for motor effort. For the first time, we investigated the quantitative effect of dopamine depletion on the motivation of motor effort in Parkinson’s disease.A total of 21 patients with Parkinson’s disease and 26 healthy controls were included. An incentivized force task was used to capture the amount of effort participants were willing to invest for different monetary incentive levels and dopamine transporter depletion in the bilateral putamen was assessed.Our results demonstrate that patients with Parkinson’s disease applied significantly less grip force than healthy controls, especially for low incentive levels. Congruously, decrease of motor effort with greater loss of putaminal dopaminergic terminals was most pronounced for low incentive levels. This signifies that putaminal dopamine is most critical to motor effort when the trade-off with the benefit is poor.Taken together, we provide direct evidence that the reduction of effortful movements in Parkinson’s disease depends on motivation and that this effect is associated with putaminal dopaminergic degeneration.
Low-grade systemic inflammation stimulates microglial turnover and accelerates the onset of Alzheimer’s-like pathology
Authors: Guerrero-Carrasco Monica , Targett Imogen , Olmos-Alonso Adrian , Vargas-Caballero Mariana , Gomez-Nicola Diego 
Published: March 2024

ABSTRACTSeveralin vivostudies have shown that systemic inflammation, mimicked by LPS, triggers an inflammatory response in the CNS, driven by microglia, characterised by an increase in inflammatory cytokines and associated sickness behaviour. However, most studies induce relatively high systemic inflammation, not directly compared with the more common low grade inflammatory events experienced in humans during the life course. Using mice, we investigated the effects of low-grade systemic inflammation during an otherwise healthy early life, and how this may pre-condition the onset and severity of Alzheimer’s disease (AD)-like pathology. Our results indicate that low grade systemic inflammation induces sub-threshold brain inflammation and promotes microglial proliferation driven by the CSF1R pathway, contrary to the effects caused by high systemic inflammation. In addition, repeated systemic challenges with low grade LPS induce disease-associated microglia. Finally, using an inducible model of AD-like pathology (Line 102 mice), we observed that pre-conditioning with repeated doses of low-grade systemic inflammation, prior to APP induction, promotes a detrimental effect later in life, leading to an increase in Aβ accumulation and disease-associated microglia. These results support the notion that episodic low grade systemic inflammation has the potential to influence the onset and severity of age-related neurological disorders, such as Alzheimer’s disease.
Evaluation of Gene Set Enrichment Analysis (GSEA) tools highlights the value of single sample approaches over pairwise for robust biological discovery
Authors: Bull Courtney , Byrne Ryan M , Fisher Natalie C , Corry Shania M , Amirkhah Raheleh , Edwards Jessica , Hillson Lily , Lawler Mark , Ryan Aideen , Lamrock Felicity , Dunne Philip D , Malla Sudhir B 
Published: March 2024

AbstractBackgroundGene set enrichment analysis (GSEA) tools can be used to identify biological insights from transcriptional datasets and have become an integral analysis within gene expression-based cancer studies. Over the years, additional methods of GSEA-based tools have been developed, providing the field with an ever-expanding range of options to choose from. Although several studies have compared the statistical performance of these tools, the downstream biological implications that arise when choosing between the range of pairwise or single sample forms of GSEA methods remain understudied.MethodsIn this study, we compare the statistical and biological interpretation of results obtained when using a variety of pre-ranking methods and options for pairwise GSEA and fast GSEA (fGSEA), alongside single sample GSEA (ssGSEA) and gene set variation analysis (GSVA). These analyses are applied to a well-established cohort of n=215 colon tumour samples, using the clinical feature of cancer recurrence status, non-relapse (NR) and relapse (R), as an initial exemplar, in conjunction with the Molecular Signatures Database “Hallmark” gene sets.ResultsDespite minor fluctuations in statistical performance, pairwise analysis revealed remarkably similar results when deployed using a range of gene pre-ranking methods or across a range of choices of GSEA versus fGSEA, with the same well-established prognostic signatures being consistently returned as significantly associated with relapse status. In contrast, when the same statistically significant signatures, such as Interferon Gamma Response, were assessed using ssGSEA and GSVA approaches, there was a complete absence of biological distinction between these groups (NR and R).ConclusionsData presented here highlights how pairwise methods can overgeneralise biological enrichment within a group, assigning strong statistical significance to gene sets that may be inadvertently interpreted as equating to distinct biology. Importantly, single sample approaches allow users to clearly visualise and interpret statistical significance alongside biological distinction between samples within groups-of-interest; thus, providing a more robust and reliable basis for discovery research.
The dynamin-related protein Dyn2 is essential for both apicoplast and mitochondrial fission inPlasmodium falciparum
Authors: Morano Alexander A. , Xu Wei , Shadija Neeta , Dvorin Jeffrey D. , Ke Hangjun 
Published: March 2024

SummaryDynamins, or dynamin-related proteins (DRPs), are large mechano-sensitive GTPases mediating membrane dynamics or organellar fission/fusion events.Plasmodium falciparumencodes three dynamin-like proteins whose functions are poorly understood. Here, we demonstrate that PfDyn2 mediates both apicoplast and mitochondrial fission. Using super-resolution and ultrastructure expansion microscopy, we show that PfDyn2 is expressed in the schizont stage and localizes to both the apicoplast and mitochondria. Super-resolution long-term live cell microscopy shows that PfDyn2-deficient parasites cannot complete cytokinesis because the apicoplast and mitochondria do not undergo fission. Further, the basal complex or cytokinetic ring inPlasmodiumcannot fully contract upon PfDyn2 depletion, a phenotype secondary to physical blockage of undivided organelles in the middle of the ring. Our data suggest that organellar fission defects result in aberrant schizogony, generating unsuccessful merozoites. The unique biology of PfDyn2, mediating both apicoplast and mitochondrial fission, has not been observed in other organisms possessing two endosymbiotic organelles.HighlightsPfDyn2 is essential for schizont-stage development.PfDyn2 mediates both apicoplast and mitochondrial fission.Deficiency of PfDyn2 leads to organellar fission failures and blockage of basal complex contraction.Addition of apicoplast-derived metabolite IPP does not rescue the growth defects.
A λ-dynamics investigation of insulinWakayamaand other A3 variant binding affinities to the insulin receptor
Authors: Barron Monica P. , Vilseck Jonah Z. 
Published: March 2024

ABSTRACTInsulinWakayamais a clinical insulin variant where a conserved valine at the third residue on insulin’s A chain (ValA3) is replaced with a leucine (LeuA3), impairing insulin receptor (IR) binding by 140-500 fold. This severe impact on binding from such a subtle modification has posed an intriguing problem for decades. Although experimental investigations of natural and unnatural A3 mutations have highlighted the sensitivity of insulin-IR binding to minor changes at this site, an atomistic explanation of these binding trends has remained elusive. We investigate this problem computationally using λ-dynamics free energy calculations to model structural changes in response to perturbations of the ValA3side chain and to calculate associated relative changes in binding free energy (ΔΔGbind). TheWakayamaLeuA3mutation and seven other A3 substitutions were studied in this work. The calculated ΔΔGbindresults showed high agreement compared to experimental binding potencies with a Pearson correlation of 0.88 and a mean unsigned error of 0.68 kcal/mol. Extensive structural analyses of λ-dynamics trajectories revealed that critical interactions were disrupted between insulin and the insulin receptor as a result of the A3 mutations. This investigation also quantifies the effect that adding an A3 Cδatom or losing an A3 Cγatom has on insulin’s binding affinity to the IR. Thus, λ-dynamics was able to successfully model the effects of subtle modifications to insulin’s A3 side chain on its protein-protein interactions with the IR and shed new light on a decades-old mystery: the exquisite sensitivity of hormone-receptor binding to a subtle modification of an invariant insulin residue.SIGNIFICANCE STATEMENTThis work addresses a decades-old question of how subtle modifications to insulin’s A3 side chain affects its binding affinity to the insulin receptor. λ-Dynamics computed free energies of binding match experimental activity trends with high accuracy. Atomistic insights into hormone-receptor protein-protein interactions were obtained through a detailed investigation of λ-dynamic trajectories. This work quantifies the effects of adding and removing atoms to insulin’s conserved A3 residue and identifies clear conformational preferences for insulin A3 residues when bound to the insulin receptor.
Seasonal variation of behavioural thermoregulation in the Spotted Salamander (Ambystoma maculatum)
Authors: Giacometti Danilo , Tattersall Glenn J. 
Published: March 2024

AbstractMounting evidence suggests that temperature seasonality plays a pivotal role in shaping the thermal biology of ectotherms. However, we still have a limited understanding of how amphibians maintain thermal balance in the face of varying temperatures, especially in fossorial species. Due to thermal buffering underground, theory predicts relaxed selection pressure over thermoregulation in fossorial ectotherms. As a result, fossorial ectotherms typically show low thermoregulatory precision and low evidence of thermotactic behaviours when tested in laboratory thermal gradients. In this study, we evaluated how temperature selection (Tsel) and behavioural thermoregulation differed between seasons in the fossorial Spotted Salamander (Ambystoma maculatum). By comparing thermoregulatory parameters between the activity and overwintering seasons, we provide evidence thatA.maculatumengages in active behavioural thermoregulation despite its fossorial habit. In both seasons, we foundTselto be consistently offset higher than prevailing thermal conditions. Thermoregulation differed between seasons, with salamanders having higherTseland showing greater evidence of thermophilic behaviours in the active season compared to the overwintering season. Our study highlights that the combination of behavioural and thermal biology measurements is a necessary step to better understand the mechanisms that underlie body temperature control in amphibians. Ultimately, our study provides a broader understanding of thermoregulation in amphibians, particularly in the context of behavioural responses to seasonality in fossorial species.Summary statementBy comparing thermoregulatory parameters between seasons, we demonstrate that the Spotted Salamander engages in active behavioural thermoregulation despite being fossorial.
Spatial contextual information modulates affordance processing and early electrophysiological markers of scene perception
Authors: Naveilhan Clément , Saulay-Carret Maud , Zory Raphaël , Ramanoël Stephen 
Published: March 2024

AbstractScene perception allows humans to extract information from their environment and plan navigation efficiently. The automatic extraction of potential paths in a scene, also referred to as navigational affordances is supported by scene-selective regions (SSRs) that enable efficient human navigation. Recent evidence suggests that the activity of these SSRs can be influenced by information from adjacent spatial memory areas. However, it remains unexplored how these contextual information could influence the extraction of bottom-up information, such as navigational affordances, from a scene and the underlying neural dynamics. Therefore, we analyzed event-related potentials (ERPs) in 26 young adults performing scene and spatial memory tasks in artificially generated rooms with varying numbers and locations of available doorways. We found that increasing the number of navigational affordances only impaired performance in the spatial memory task. ERP results showed a similar pattern of activity for both tasks, but with increased P2 amplitude in the spatial memory task compared to the scene memory. Finally, we reported no modulation of the P2 component by the number of affordances in either task. This modulation of early markers of visual processing suggests that the dynamics of SSR activity are influenced by a priori knowledge, with increased amplitude when participants have more contextual information about the perceived scene. Overall, our results suggest that prior spatial knowledge about the scene, such as the location of a goal, modulates early cortical activity associated with scene-selective regions, and that this information may interact with bottom-up processing of scene content, such as navigational affordances.