bluuebunny/crossref_metadata_2025 huggingface dataset:
Eigengenereveals invariant global spatial patterns across mouse and fish brain development
Authors: Kerstjens Stan , Engert Florian , Zador Anthony M , Douglas Rodney J
Published: September 2024

Development from a zygote to an adult organism involves complex interactions among thousands of genes. These genes exhibit highly dynamic expression across space and time. Here we report a striking simplicity amidst this complexity: Despite individual gene expression variability, theeigengene—the principal component of gene expression—exhibits an invariant global spatial pattern throughout the embryonic and post-natal stages of the mouse brain. Furthermore, the mouse pattern is observed also in the larval zebrafish, revealing that eigengene expression is conserved over 400 million years of evolution. We show that the eigengene pattern can be explained by a simple lineage model in which daughter cells’ gene expression is similar to that of their parent, but cannot be explained by one in which gene expression arises through local cellular signaling. The constrained lineage gives rise naturally to a global eigengene expression hierarchy that could aid in the formation of a spatial hierarchy of long-range signal gradients. We propose that lineage thus induces an address-like organization, which could have been co-opted by evolution for developmental processes that require positional information over a wide range of spatial scales, such as tissue patterning and axon navigation.
Increased neuronal expression of the early endosomal adaptor APPL1 leads to endosomal and synaptic dysfunction with cholinergic neurodegeneration
Authors: Jiang Ying , Sachdeva Kuldeep , Goulbourne Chris N. , Berg Martin J. , Peddy James , Stavrides Philip H. , Pensalfini Anna , Pawlik Monika , Whyte Lauren , Balapal Basavaraj S. , Shivakumar Subbanna , Bleiwas Cynthia , Smiley John F. , Mathews Paul M. , Nixon Ralph A.
Published: September 2024

Dysfunction of the endolysosomal system within neurons is a prominent feature of Alzheimer’s disease (AD) pathology. Multiple AD-risk factors are known to cause hyper-activity of the early-endosome small GTPase rab5, resulting in neuronal endosomal pathway disruption. APPL1, an important rab5 effector protein, is an interface between endosomal and neuronal function through a rab5-activating interaction with the BACE1-generated C-terminal fragment (βCTF or C99) of the amyloid precursor protein (APP), a pathogenic APP fragment generated within endolysosomal compartments. To better understand the role of APPL1 in the AD endosomal phenotype, we generated a transgenic mouse model over-expressing human APPL1 within neurons (Thy1-APPL1 mice). Consistent with the important endosomal regulatory role of APPL1, Thy1-APPL1 mice have enlarged neuronal early endosomes and increased synaptic endocytosis due to increased rab5 activation. We additionally demonstrate pathological consequences of APPL1 overexpression, including functional changes in hippocampal long-term potentiation (LTP) and long-term depression (LTD), as well as degeneration of the large projection cholinergic neurons of the basal forebrain and impairment of hippocampal-dependent memory. Our findings show that increased neuronal APPL1 levels lead to a cascade of pathological effects within neurons, including early endosomal alterations, synaptic dysfunction, and neurodegeneration. Multiple risk factors and molecular regulators, including APPL1 activity, are known to contribute to the endosomal dysregulation seen in the early stages of AD, and these findings further highlight the shared pathobiology and consequences to a neuron of early endosomal pathway disruption.

Significance Statement

Dysfunction in the endolysosomal system within neurons is a key feature of Alzheimer’s disease (AD). Multiple AD risk factors lead to hyperactivity of the early-endosome GTPase rab5, disrupting neuronal pathways including the cholinergic circuits involved early in memory decline. APPL1, a crucial rab5 effector, connects endosomal and neuronal functions through its interaction with a specific amyloid precursor protein (APP) fragment generated within endosomes. To understand APPL1’s role, a transgenic mouse model over-expressing human APPL1 in neurons (Thy1-APPL1 mice) was developed. These mice show enlarged early endosomes and increased synaptic endocytosis due to rab5 activation, resulting in impaired hippocampal long-term potentiation and depression, the degeneration of basal forebrain cholinergic neurons, and memory deficits, highlighting a pathological cascade mediated through APPL1 at the early endosome.
Comprehensive Mutational Landscape Analysis of Monkeypox Virus Proteome
Authors: Ozaktas Tugba , Dizkirici Ayten , Carbone Alessandra , Tekpinar Mustafa
Published: September 2024

We present a comprehensive computational analysis of the single point mutational landscapes of the Monkeypox virus (MPXV) proteome. We reconstructed full single-point mutational landscapes of 171 MPXV proteins using two advanced mutational effect predictors, ESCOTT and iGEMME, selected for their superior performance on viral proteins, assessed by benchmarking against the experimental data in the ProteinGym (v1.0.0) dataset. A recent MPXV strain sequenced in July 2024 was used as the reference genome. Multiple sequence alignments and protein structures were generated using Colabfold v1.5.5, and the predicted structures were evaluated with pLDDT metric, secondary structure predictions, and comparisons with available experimental data, ensuring high confidence in the structural models. To prioritize the most mutation-sensitive proteins within the large MPXV proteome as prime candidates for drug or vaccine development, we introduced a novel, interpretable metric: Average Gene Mutation Sensitivity (AGMS). Among the top 20 identified proteins, several were membrane-associated proteins, expected to be important for viral interactions with the hosts. This analysis provides a valuable resource for assessing the impact of new MPXV variants and guiding therapeutic strategies. This pioneering study underscores the significance of understanding MPXV evolution in the context of the ongoing global health crisis and offers a robust computational framework to support this effort.
A unified rodent atlas reveals the cellular complexity and evolutionary divergence of the dorsal vagal complex
Authors: Hes Cecilia , Tomlinson Abigail J. , Michielsen Lieke , Murdoch Hunter J. , Soltani Fatemeh , Kokoeva Maia , Sabatini Paul V.
Published: September 2024

The dorsal vagal complex (DVC) is a region in the brainstem comprised of an intricate network of specialized cells responsible for sensing and propagating many appetite-related cues. Understanding the dynamics controlling appetite requires deeply exploring the cell types and transitory states harbored in this brain site. We generated a multi-species DVC cell atlas using single nuclei RNAseq (sn-RNAseq), by curating and harmonizing mouse and rat data, which includes >180,000 cells and 123 cell identities at 5 granularities of cellular resolution. We report unique DVC features such asKcnj3expression in Ca+-permeable astrocytes as well as new cell populations like neurons co-expressingThandCck, and a leptin receptor-expressing neuron population in the rat area postrema which is marked by expression of the progenitor marker,Pdgfra. In summary, our findings demonstrate a high degree of complexity within the DVC and provide a valuable tool for the study of this metabolic center.
Decoding Parametric Grip-Force Anticipation from fMRI-Data
Authors: Caccialupi Guido , Schmidt Timo Torsten , Nierhaus Till , Wesolek Sara , Esmeyer Marlon , Blankenburg Felix
Published: September 2024

Previous functional magnetic resonance imaging (fMRI) studies have shown that activity in premotor and parietal brain-regions covaries with the intensity of upcoming grip-force. However, it remains unclear how information about the intended grip-force intensity is initially represented and subsequently transformed into a motor code before motor-execution. In this fMRI study, we used multivoxel pattern analysis (MVPA) to decode where and when information about grip-force intensities is parametrically coded in the brain. Human participants performed a delayed grip-force task in which one of four cued levels of grip-force intensity had to be maintained in working memory (WM) during a 9-second delay-period preceding motor execution. Using time-resolved MVPA, with a searchlight approach and support vector regression (SVR), we tested which brain regions exhibit multivariate WM codes of anticipated grip-force intensities. During an early delay-period, we observed above-chance decoding in the ventromedial prefrontal cortex (vmPFC). During a late delay-period, we found a network of action-specific brain regions, including the bilateral intraparietal sulcus (IPS), left dorsal premotor cortex (l-PMd) and supplementary motor areas (SMA). Additionally, cross-regression decoding was employed to test for temporal generalization of activation patterns between early and late delay-periods with those during cue presentation and motor execution. Cross-regression decoding indicated temporal generalization to the cue-period in the vmPFC, and to motor-execution in the l-IPS and l-PMd. Together, these findings suggest that the WM representation of grip-force intensities undergoes a transformation where the vmPFC encodes information about the intended grip-force, which is subsequently converted into a motor code in the l-IPS and l-PMd before execution.
EFFECTS OF SPINAL TRANSECTION AND LOCOMOTOR SPEED ON MUSCLE SYNERGIES OF THE CAT HINDLIMB
Authors: Klishko Alexander N. , Harnie Jonathan , Hanson Claire E. , Rahmati S. Mohammadali , Rybak Ilya A. , Frigon Alain , Prilutsky Boris I.
Published: September 2024

It was suggested that during locomotion, the nervous system controls movement by activating groups of muscles, or muscle synergies. Analysis of muscle synergies can reveal the organization of spinal locomotor networks and how it depends on the state of the nervous system, such as before and after spinal cord injury, and on different locomotor conditions, including a change in speed. The goal of this study was to investigate the effects of spinal transection and locomotor speed on hindlimb muscle synergies and their time-dependent activity patterns in adult cats. EMG activities of 15 hindlimb muscles were recorded in 9 adult cats of either sex during tied-belt treadmill locomotion at speeds of 0.4, 0.7, and 1.0 m/s before and after recovery from a low thoracic spinal transection. We determined EMG burst groups using cluster analysis of EMG burst onset and offset times and muscle synergies using non-negative matrix factorization. We found five major EMG burst groups and five muscle synergies in each of six experimental conditions (2 states x 3 speeds). In each case, the synergies accounted for at least 90% of muscle EMG variance. Both spinal transection and locomotion speed modified subgroups of EMG burst groups and the composition and activation patterns of selected synergies. However, these changes did not modify the general organization of muscle synergies. Based on the obtained results, we propose an organization for a pattern formation network of a two-level central pattern generator that can be tested in neuromechanical simulations of spinal circuits controlling cat locomotion.
Neuronal lipid droplets play a conserved and sex-biased role in maintaining whole-body energy homeostasis
Authors: Manceau Romane , Majeur Danie , Cherian Celena M. , Miller Colin J. , Wat Lianna W. , Fisher Jasper D. , Labarre Audrey , Hollman Serena , Prakash Sanjana , Audet Sébastien , Chao Charlotte F. , Depaauw-Holt Lewis , Rogers Benjamin , Bosson Anthony , Xi Joyce J.Y. , Callow Catrina A.S. , Yoosefi Niyoosha , Shahraki Niki , Xia Yi Han , Hui Alisa , VanderZwaag Jared , Bouyakdan Khalil , Rodaros Demetra , Kotchetkov Pavel , Daneault Caroline , Fallahpour Ghazal , Tetreault Martine , Tremblay Marie-Ève , Ruiz Matthieu , Lacoste Baptiste , Parker J.A. , Murphy-Royal Ciaran , Huan Tao , Fulton Stephanie , Rideout Elizabeth J. , Alquier Thierry
Published: September 2024

ABSTRACT

Lipids are essential for neuron development and physiology. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear. Here, we combine invertebrate and vertebrate models to establish the presence and functional significance of neuronal lipid droplets (LD)in vivo. We find that LD are normally present in neurons in a non-uniform distribution across the brain, and demonstrate triglyceride metabolism enzymes and lipid droplet-associated proteins control neuronal LD formation through both canonical and recently-discovered pathways. Appropriate LD regulation in neurons has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically neurons that couple environmental cues with energy homeostasis. Mechanistically, LD-derived lipids support neuron function by providing phospholipids to sustain mitochondrial and endoplasmic reticulum homeostasis. Together, our work identifies a conserved role for LD as the organelle that coordinates lipid management in neurons, with implications for our understanding of mechanisms that preserve neuronal lipid homeostasis and function in health and disease.

HIGHLIGHTS

Lipid droplets (LD) normally form in neurons across species Neuronal LD are regulated by a conserved gene network

Neuronal LD regulation plays a conserved and sex-biased role in maintaining energy homeostasis

LD regulation supports ER and mitochondrial function in hunger-activated neurons

GRAPHICAL ABSTRACT
Simulated ischemia in live cerebral slices is mimicked by opening the Na+/K+pump: clues to the generation of spreading depolarization
Authors: Kim Danielle , Gagolewicz Peter , McQueen Sydney , Latour Hannah , Tresidder Kaitlyn , Jarvis Cathryn R. , Andrew R. David
Published: September 2024

The gray matter of the higher brain undergoes spreading depolarization (SD) in response to the increased metabolic demand of ischemia, promoting acute neuronal injury and death. The mechanism linking ischemic failure of the Na+/K+ATPase (NKA) to the subsequent onset of a large inward current driving SD in neurons has remained a mystery because blockade of conventional channels does not prevent SD nor ischemic death. The marine poison palytoxin (PLTX) specifically binds the NKA transporter at extremely low concentrations, converting it to an open cationic channel, causing sudden neuronal Na+influx and K+efflux. Pump failure and induction of a strong inward current should induce dramatic SD-like activity. Indeed,1-10 nM PLTX applied to live coronal brain slices induces a propagating depolarization remarkably like SD induced by oxygen/glucose deprivation (OGD) as revealed by imaging. This PLTX depolarization (PD) mimicked other effects of OGD. In neocortex, as the elevated LT front passed by an extracellular pipette, a distinct negative DC shift was recorded, indicating cell depolarization, whether induced by OGD or by bath PLTX. Either treatment induced strong SD-like responses in the same higher and lower brain regions. Further, we imaged identical real-time OGD-SD or PD effects upon live pyramidal neurons using 2-photon microscopy. Taken together, these findings support our proposal that, like most biological poisons, PLTX mimics (and takes advantage of) a biological process,ie is brain ischemia. An endogenous PLTX-like molecule may open the NKA to evoke Na+influx/K+efflux that drive SD and the ensuing neuronal damage in its wake.

New and Noteworthy

With stroke, traumatic brain injury, or sudden cardiac arrest, there is no therapeutic drug to aid brain protection and recovery. Within 2 minutes of severe ischemia, a wave of spreading depolarization (SD) propagates through gray matter. More SDs arise over hours, expanding injury. This period represents a therapeutic window to inhibit recurring SD and reduce damage but we do not understand the molecular sequence. Here we argue for a novel molecule to target.
T1234: A distortion-matched structural scan solution to misregistration of high resolution fMRI data
Authors: Kan Chung (Kenny) , Stirnberg Rüdiger , Montequin Marcela , Gulban Omer Faruk , Morgan A Tyler , Bandettini Peter , Huber Laurentius (Renzo)
Published: September 2024

Purpose

High-resolution fMRI at 7T is challenged by suboptimal alignment quality between functional data and structural scans. This study aims to develop a rapid acquisition method that provides distortion-matched, artifact-mitigated structural reference data.

Methods

We introduce an efficient sequence protocol termed T1234, which offers adjustable distortions. This approach involves a T1-weighted 2-inversion 3D-EPI sequence with four spatial encoding directions optimized for high-resolution fMRI. A forward Bloch model was used for T1 quantification and protocol optimization. Twenty participants were scanned at 7T using both structural and functional protocols to evaluate the utility of T1234.

Results

Results from two protocols are presented. A fast distortion-free protocol reliably produced whole-brain segmentations at 0.8mm isotropic resolution within 3:00-3:40 minutes. It demonstrates robustness across sessions, participants, and three different 7T SIEMENS scanners. For a protocol with geometric distortions that matched functional data, T1234 facilitates layer-specific fMRI signal analysis with enhanced laminar precision.

Conclusion

This structural mapping approach enables precise registration with fMRI data. T1234 has been successfully implemented, validated, and tested, and is now available to users at our center and at over 50 centers worldwide.
Morphological profiling reveals neuroprotection via mitochondrial uncoupling in human dopaminergic neurons
Authors: Gorgogietas Vyron , Weiss Amélie , Cousin Loïc , Hoffmann David , Schmitt Karen , Ogier Arnaud , Barbuti Peter A. , Santos Bruno F.R. , Boussaad Ibrahim , Wittich Annika , Zaliani Andrea , Pless Ole , Krüger Rejko , Sommer Peter , Wilbertz Johannes H.
Published: September 2024

Parkinson’s disease (PD) involves multiple pathological processes in midbrain dopaminergic (mDA) neurons, including protein degradation defects, vesicular trafficking disruption, endolysosomal dysfunction, mitochondrial issues, and oxidative stress. Current PD models often lack complexity and focus on single phenotypes. We used patient-derived SNCA triplication (SNCA-4x) and isogenic control (SNCA-corr) mDA neurons, applying high-content imaging-based morphological profiling to identify and rescue multiple phenotypes. Screening 1,020 compounds, we identified top-scoring compounds that restored healthy profiles in SNCA-4x neurons, increasing Tyrosine hydroxylase (TH) and decreasing α-synuclein (αSyn) levels. Several hits were linked to mitochondrial biology. Tyrphostin A9, a mitochondrial uncoupler, and several of its structural analogues decreased ROS levels, normalized mitochondrial membrane potential, and increased respiration. Western blotting confirmed that Tyrphostin A9 reduces αSyn levels. Our study highlights the neuroprotective potential of mild mitochondrial uncoupling in mDA neurons.
Capillary-scale Microvessel Imaging with High-frequency Ultrasound Localization Microscopy in Mouse Brain
Authors: Lowerison Matthew R. , Wang Yike , Lin Bing-Ze , Huang Zhe , Yan Dongliang , Shin YiRang , Song Pengfei
Published: September 2024

Ultrasound localization microscopy is a super-resolution vascular imaging technique which has garnered substantial interest as a tool for small animal neuroimaging, neuroscience research, and the characterization of vascular pathologies. In the pursuit of increasingly high-fidelity reconstructions of microvasculature, there remains several outstanding questions concerning this sub-diffraction imaging technology, including the accurate reconstruction of microvessels approaching the capillary scale and the pragmatic challenges associated with long data acquisition times. In the context of small animal neurovascular imaging, we posit that increasing the ultrasound imaging frequency is a straightforward approach to enable higher concentrations of microbubble contrast agents, thus increasing the likelihood of microvascular/capillary mapping and decreasing the imaging duration. We demonstrate that higher frequency imaging results in improved ULM fidelity and more efficient microbubble localization due to a smaller microbubble point-spread function that is easier to localize, and which can achieve a higher localizable concentration within the same unit volume of tissue. A select example ofin vivocapillary-level vascular reconstruction is demonstrated for the highest frequency imaging probe, which has substantial implications for neuroscientists investigating microvascular function in disease states, regulation, and brain development. High frequency ULM yielding a spatial resolution of 7.1μm, as measured by Fourier ring correlation, throughout the entire depth of the brain, highlighting this technology as a highly relevant tool for neuroimaging research.
Modulating DNA Polα Enhances Cell Reprogramming Across Species
Authors: Ranjan Rajesh , Ma Binbin , Gleason Ryan J. , Liao Yijun , Bi Yingshan , Davis Brendon E. M. , Yang Guanghui , Clark Maggie , Mahajan Vikrant , Condon Madison , Broderick Nichole A. , Chen Xin
Published: September 2024

As a fundamental biological process, DNA replication ensures the accurate copying of genetic information. However, the impact of this process on cellular plasticity in multicellular organisms remains elusive. Here, we find that reducing the level or activity of a replication component, DNA Polymerase α (Polα), facilitates cell reprogramming in diverse stem cell systems across species. InDrosophilamale and female germline stem cell lineages, reducing Polα levels using heterozygotes significantly enhances fertility of both sexes, promoting reproductivity during aging without compromising their longevity. Consistently, inC. elegansthepolaheterozygous hermaphrodites exhibit increased fertility without a reduction in lifespan, suggesting that this phenomenon is conserved. Moreover, in male germline and female intestinal stem cell lineages ofDrosophila,polαheterozygotes exhibit increased resistance to tissue damage caused by genetic ablation or pathogen infection, leading to enhanced regeneration and improved survival during post-injury recovery, respectively. Additionally, fine tuning of an inhibitor to modulate Polα activity significantly enhances the efficiency of reprogramming human embryonic fibroblasts into induced pluripotent cells. Together, these findings unveil novel roles of a DNA replication component in regulating cellular reprogramming potential, and thus hold promise for promoting tissue health, facilitating post-injury rehabilitation, and enhancing healthspan.
Functional localization of visual motion area FST in humans
Authors: Wen Puti , Ezzo Rania , Thompson Lowell W , Rosenberg Ari , Landy Michael S , Rokers Bas
Published: September 2024

The fundus of the superior temporal sulcus (FST) in macaques is implicated in the processing of complex motion signals, yet a human homolog remains elusive. Here we considered potential localizers and evaluated their effectiveness in delineating putative FST (pFST), from hMT and MST, two nearby motion-sensitive areas in humans. Nine healthy participants underwent scanning sessions with 2D and 3D motion localizers, as well as population receptive field (pRF) mapping. We observed consistent anterior and inferior activation relative to hMT and MST in response to stimuli that contained coherent 3D, but not 2D, motion. Motion opponency and myelination measures further validated the functional and structural distinction between pFST and hMT/MST. At the same time, standard pRF mapping techniques that reveal the visual field organization of hMT/MST proved suboptimal for delineating pFST. Our findings provide a robust framework for localizing pFST in humans, and underscore its distinct functional role in motion processing.
Increased protein kinase Mζ expression by Minocycline and N-acetylcysteine restores late-phase long-term potentiation and spatial learning after closed head injury in mice
Authors: Nikulina Elena , Tsokas Panayiotis , Whitney Kristen , Tcherepanov Andrew , Hsieh Changchi , Sacktor Todd C. , Bergold Peter J.
Published: September 2024

Cognitive deficits frequently arise after traumatic brain injury. The murine closed head injury (CHI) models these deficits since injured mice cannot acquire Barnes maze. Dosing of minocycline plus N-acetylcysteine beginning 12 hours post-CHI (MN12) restores Barnes maze acquisition by an unknown mechanism. Increased hippocampal synaptic efficacy is needed to acquire Barnes maze, synaptic long-term potentiation (LTP) models this increased synaptic efficacyin vitro. LTP has an early phase (E-LTP) lasting up to one hour that is mediated by second messengers that is followed by a late phase (L-LTP) that needs new synthesis of protein kinase M zeta (PKMζ). PKMζ has constitutive kinase activity because it lacks the autoinhibitory regulatory domain found in other PKCs. Due to its constitutive activity, the amount of PKMζ kinase activity is determined by PKMζ protein levels. We report that CHI bilaterally decreases PKMζ levels in the CA3 and CA1 hippocampus. MN12 increases CA1 PKMζ expression. CHI inhibits E-LTP in slices from the ipsilesional hippocampus and inhibits L-LTP in slices from both hippocamppi. MN12 treatment reestablishes both E-LTP and L-LTP in slices from the injured MN12-treated hippocampus. The restoration of L-LTP from injured MN12-treated hippocampus is mediated by PKMζ because L-LTP is blocked by the specific PKMζ inhibitor, ζ-stat. Hippocampal ζ-stat infusions also prevents Barnes maze acquisition in injured, MN12-treated mice. These data suggest that post-injury minocycline plus N-acetylcysteine targets PKMζ to improve synaptic plasticity and cognition in mice with closed-head injury.
Resting-state hyper- and hypo-connectivity in early schizophrenia: which tip of the iceberg should we focus on?
Authors: Tomecek David , Kolenic Marian , Rehak Buckova Barbora , Tintera Jaroslav , Spaniel Filip , Horacek Jiri , Hlinka Jaroslav
Published: September 2024

In this study, we explore the intricate landscape of brain connectivity in the early stages of schizophrenia, focusing on the patterns of hyper- and hypoconnectivity. Despite existing literature’s support for altered functional connectivity (FC) in schizophrenia, inconsistencies and controversies persist regarding specific dysconnections.

Leveraging a large sample of 100 first-episode schizophrenia patients (42 females/58 males) and 90 healthy controls (50 females/40 males), we compare the functional connectivity (FC) across 90 brain regions of the Automated Anatomical Labeling atlas. We inspected the effects of medication and examined the association between FC changes and duration of illness as well as symptom severity of the disorder. Our approach also includes a comparative analysis of two denoising strategies for functional magnetic resonance imaging data.

In the group of patients, 247 region pairs exhibited greater FC, while 134 region pairs showed reduced FC compared to healthy controls. We found a significant correlation between patients’ FC and symptom severity, and antipsychotic medication. However, when a more moderate denoising scheme was used, the results became significantly skewed towards hypoconnectivity in patients. Moreover, there was no relationship between FC and medication or symptom severity in the case of the moderate denoising scheme.

Altogether, we found an overall balanced picture of both hyper- and hypoconnectivity in patients with schizophrenia compared to the healthy controls and unraveled a link between FC in patients and the severity of symptoms and medication. Notably, the balanced picture of FC gets significantly disrupted when less stringent data denoising is applied.
Fine decomposition of rodent behavior via unsupervised segmentation and clustering of inertial signals
Authors: Fayat Romain , Sarraudy Marie , Léna Clément , Popa Daniela , Latouche Pierre , Dugué Guillaume P
Published: September 2024

Decomposing behavior into elementary components remains a central challenge in computational neuroethology. The current standard in laboratory animals involves multi-view video tracking, which, while providing unparalleled access to full-body kinematics, imposes environmental constraints, is data-intensive, and has limited scalability. We present an alternative approach using inertial sensors, which capture high-resolution, environment-independent, and compact three-dimensional kinematic data, and are commonly integrated into rodent neurophysiological devices. Our analysis pipeline leverages unsupervised, computationally efficient change-point detection to break down inertial time series into variable-length, statistically homogeneous segments. These segments are then grouped into candidate behavioral motifs through high-dimensional, model-based probabilistic clustering. We demonstrate that this approach achieves detailed rodent behavioral mapping using head inertial data. Identified motifs, corroborated by video recordings, include orienting movements, grooming components, locomotion, and olfactory exploration. Higher-order behavioral structures can be accessed by applying a categorical hidden Markov model to the motif sequence. Additionally, our pipeline detects both overt and subtle motor changes in a mouse model of Parkinson's disease and levodopa-induced dyskinesia, highlighting its value for behavioral phenotyping. This methodology offers the possibility of conducting high-resolution, observer-unbiased behavioral analysis at minimal computational cost from easily scalable and environmentally unconstrained recordings.
Deep learning uncovers sequence-specific amplification bias in multi-template PCR
Authors: Gimpel Andreas L. , Fan Bowen , Chen Dexiong , Wölfle Laetitia O. D. , Horn Max , Meng-Papaxanthos Laetitia , Antkowiak Philipp L. , Stark Wendelin J. , Christen Beat , Borgwardt Karsten , Grass Robert N.
Published: September 2024

Multi-template polymerase chain reaction is a key step in many amplicon sequencing protocols enabling parallel amplification of diverse DNA molecules sharing common adapters in applications, ranging as wide as quantitative molecular biology and DNA data storage. However, this process results in a skewed amplicon abundance, due to sequence-specific amplification biases. In this study, one-dimensional convolutional neural networks (1D-CNNs) were trained on synthetic DNA pools to learn the PCR amplification efficiency of individual templates. These 1D-CNN models can predict poorly amplifying templates based solely on sequence information, achieving an AUROC/AUPRC of up to 0.88/0.44 with very imbalanced prevalence of 2%, thereby greatly outperforming baseline models relying only on GC content and nucleotide frequency as predictors. A new, general-purpose framework for interpreting deep learning models, termedCluMoprovides mechanistic insights into the amplification biases. Most strikingly, specific amplification reactions were identified as suffering from adaptor-template self-priming a mechanism previously disregarded in PCR.
The macaque ventral intraparietal functional connectivity patterns reveal an anterio-posterior specialization mirroring that described in human ventral intraparietal area
Authors: Sheng Wei-An , Clavagnier Simon , Froesel Mathilda , Vanduffel Wim , Heed Tobias , Hamed Suliann Ben
Published: September 2024

The macaque monkey’s ventral intraparietal area (VIP) in the intraparietal sulcus (IPS) responds to visual, vestibular, tactile and auditory signals and is involved in higher cognitive functions including the processing of peripersonal space. In humans, VIP appears to have expanded into three functionally distinct regions. Macaque VIP has been divided cytoarchitonically into medial and lateral parts; however, no functional specialization has so far been associated with this anatomical division. Functional MRI suggests a functional gradient along the anterior-posterior axis of the macaque IPS: anterior VIP shows visio-tactile properties and face preference, whereas posterior VIP responds to large-field visual dynamic stimuli. This functional distinction matches with functional differences among the three human VIP regions, suggesting that a regional specialization may also exist within macaque VIP. Here, we characterized the ipsilateral, whole-brain functional connectivity, assessed during awake resting state, along VIP’s anterior-posterior axis by dividing VIP into three regions of interest (ROIs). The functional connectivity profiles of the three VIP ROIs resembled anatomical connectivity profiles obtained by chemical tracing. Anterior VIP was functionally connected to regions associated with motor, tactile, and proprioceptive processing and with regions involved in reaching, grasping, and processing peripersonal space. Posterior VIP had the strongest functional connectivity to regions involved in motion processing and eye movements. These profiles are consistent with the connectivity profiles of the anterior and posterior VIP areas identified in humans. Viewed together, resting state functional connectivity, task-related fMRI and anatomical tracing consistently suggest specific functional specializations of macaque anterior and posterior VIP. This specialization corroborates the distinction of VIP into three anatomically and functionally separate VIP areas in humans.
Exercise Evokes Retained Motor Performance without Neuroprotection in a Mouse Model of Parkinson’s Disease
Authors: Skelton Henry M. , Hyman Nathaniel , Fernandez Alejandra , Acerbo Emma , Scott Madison , Berglund Ken , Gutekunst Claire-Anne , Gross Robert E.
Published: September 2024

Exercise has been extensively studied in Parkinson’s Disease, with a particular focus on the potential for neuroprotection that has been demonstrated in animal models. While this preclinical work has provided insight into the underlying molecular mechanisms, it has not addressed the neurophysiological changes during exercise. Here, first, we tested for neuroprotective effects of adaptive wheel exercise in the 6-hydroxydopamine mouse model of Parkinson’s disease. Finding none, we probed the neurophysiology of exercise as a state of high motor function amidst an unameliorated Parkinsonian lesion. Exercise was associated with characteristic, excitatory changes in the dopamine-depleted substantia nigra, which could be suppressed along with exercise itself by dopamine receptor blockade. Going forward, the functional state evoked by exercise merits further study, as it may represent an optimal target for neuromodulation, even if the underlying pathology cannot be averted.
The Cellular and Extra-Cellular Proteomic Signature of Human Dopaminergic Neurons Carrying the LRRK2 G2019S Mutation
Authors: Knab Felix , Guaitoli Giambattista , Jarboui Mohamed Ali , von Zweydorf Felix , Isik Fatma Busra , Klose Franziska , Rajkumar Anto Praveen , Gasser Thomas , Gloeckner Christian Johannes
Published: September 2024

Extracellular vesicles are easily accessible in various biofluids and allow the assessment of disease-related changes of the proteome. This has made them a promising target for biomarker studies, especially in the field of neurodegeneration where access to diseased tissue is very limited. Genetic variants in the LRRK2 gene have been linked to both familial and sporadic forms of Parkinson’s disease. With LRRK2 inhibitors entering clinical trials, there is an unmet need for biomarkers that reflect LRRK2-specific pathology and target engagement. In this study, we used induced pluripotent stem cells derived from a patient with Parkinson’s disease carrying the LRRK2 G2019S mutation and an isogenic gene corrected control to generate human dopaminergic neurons. We isolated extracellular vesicles and neuronal cell lysates and characterized their proteomic signature using data-independent acquisition proteomics. We performed differential expression analysis and identified 595 significantly differentially regulated proteins in extracellular vesicles and 3205 in cell lysates. Next, we performed gene ontology enrichment analyses on the dysregulated proteins and found close association to biological processes relevant in neurodegeneration and Parkinson’s disease. Finally, we focused on proteins that were dysregulated in both the extracellular and cellular proteomes and provide a list of ten promising biomarker candidates that are functionally relevant in neurodegeneration and linked to LRRK2 associated pathology. Among those was the sonic hedgehog signaling molecule, a protein that has tightly been linked to LRRK2-related disruption of cilia function. In conclusion, we characterized the cellular and extracellular proteome of dopaminergic neurons carrying the LRRK2 G2019S mutation and propose an experimentally based list of promising biomarker candidates for future studies.
The effect of social structure on vocal flexibility in monk parakeets
Authors: Smeele Simeon Q. , Senar Juan Carlos , McElreath Mary Brooke , Aplin Lucy M.
Published: September 2024

The social complexity hypothesis argues that communicative complexity arises as a result of social complexity, with this occurring through mechanisms including plasticity and selection. Most research to date has focused on ultimate drivers of repertoire size, for example finding that cooperative breeding species exhibit larger repertoires. Until this date no study has focused on individual-level drivers of vocal diversity. Here, we examine social networks and vocalisations in wild colonial-nesting monk parakeets (Myiopsitta monachus). First, we recorded social networks for 337 individuals, relatedness for 100 individuals and matched these with 5599 vocalisations from 229 individuals over two years. Overall, we found that all individuals exhibited high contact-call diversity; however, individual-level diversity increased with age in 2020 and with number of nest mates in 2021. Call similarity was not predicted by relatedness, but individuals with stronger affiliative bonds had more dissimilar calls, suggesting an active process to sound unique among close associates. Finally, females had more diverse repertoires, producing relatively fewer contact calls across years and individuals living in larger groups had more diverse repertoires in 2021. Our results demonstrate a multi-faceted social influence on call content, diversity and repertoire diversity, exhibiting how fine-scale variation in social structure can influence expressed vocal complexity.
Unravelling the Proteomic Landscape of Imipenem Resistance inPseudomonas aeruginosa: A Comparative Investigation between Clinical and Control Strains
Authors: Eidsaa Marius , Sharma Animesh , Janasch Markus , Kuch Alicja , Skoczyńska Anna , Di Bartolomeo Francesca
Published: September 2024

The increasing prevalence of antimicrobial resistance (AMR) poses a significant challenge to global health, particularly with bacterial pathogens such asPseudomonas aeruginosa, a notorious cause of nosocomial infections. This study focuses on the comparative proteomic analysis of an imipenem-resistant strain ofP. aeruginosa, a representative of world epidemic clone ST235, and a wildtype control strain,P. aeruginosaATCC 27853, in response to varying concentrations of imipenem. Using label-free quantification (LFQ) and gene ontology (GO) enrichment analyses, we identified significant differences in the proteomic responses between the two strains (data available via ProteomeXchange with identifier PXD055744.). The clinical strain exhibited a stable proteomic profile across the imipenem gradient, suggesting pre-established and efficient resistance mechanisms that do not require extensive reconfiguration under antibiotic pressure. In contrast, the control strain showed a broader, more reactive proteomic response, particularly in proteins associated with membrane transport, stress response, and biofilm formation. Notably, uncharacterized proteins were significantly upregulated in the clinical strain, indicating potential novel resistance mechanisms. These findings highlight the distinct strategies employed by the two strains, with the clinical strain’s stable resistance mechanisms contrasting sharply with the control strain’s reactive approach. The study underscores the importance of further research into the uncharacterized proteins that may play crucial roles in antibiotic resistance, potentially leading to new therapeutic targets in the fight against AMR.

Highlights

Stable resistance mechanisms: The clinical strain ofPseudomonas aeruginosa(ST235) exhibited a stable proteomic profile across varying concentrations of imipenem, indicating pre-established and efficient resistance mechanisms.

Reactive proteomic response: The control strain (P. aeruginosaATCC 27853) showed a broader and more reactive proteomic response, particularly in proteins related to membrane transport, stress response, and biofilm formation.

Uncharacterized proteins: Significant upregulation of uncharacterized proteins in the clinical strain suggests potential novel resistance mechanisms that warrant further investigation.
Working memory predicts long-term recognition of auditory sequences: Dissociation between confirmed predictions and prediction errors
Authors: Bonetti L. , Risgaard Olsen E. , Carlomagno F. , Serra E. , Szabó S.A. , Klarlund M. , Andersen M.H. , Frausing L. , Vuust P. , Brattico E. , Kringelbach M.L. , Fernández-Rubio G.
Published: September 2024

Memory is a crucial cognitive process involving several subsystems: sensory memory (SM), short-term memory (STM), working memory (WM), and long-term memory (LTM). While each has been extensively studied, the interaction between WM and LTM, particularly in relation to predicting temporal sequences, remains largely unexplored. This study investigates the relationship between WM and LTM, and how these relate to aging and musical training. Using three datasets with a total of 244 healthy volunteers across various age groups, we examined the impact of WM on LTM recognition of novel and previously memorized musical sequences. Our results show that WM abilities are significantly related to recognition of novel sequences, with a more pronounced effect in older compared to younger adults. In contrast, WM did not similarly impact the recognition of memorized sequences, which implies that different cognitive processes are involved in handling prediction errors compared to confirmatory predictions, and that WM contributes to these processes differently. Additionally, our findings confirm that musical training enhances memory performance. Future research should extend our investigation to populations with cognitive impairments and explore the underlying neural substrates.
Tetanizing wakeful consolidation: ten-hertz repetitive visual stimulation enhances the offline gain of visual learning
Authors: Yang Xin-Yue , Zhao Chuyue , Zuo Zhentao , Li Aming , Luo Huan , He Qing , Fang Fang
Published: September 2024

Consolidation of encoded information is vital for learning and memory, often explored during sleep. However, the consolidation during post-encoding offline wakefulness remains largely uncharted, especially regarding its modulation and brain mechanisms. Here, we unraveled frequency-dependent modulatory effects of repetitive visual stimulation (RVS) on wakeful consolidation of visual learning and investigated the underlying neural substrates. After training on an orientation discrimination task, exposure to 10-Hz grating-form RVS enhanced, while 1-Hz RVS deteriorated, the discrimination performance in a subsequent retest. However, 10-Hz uniform-disk RVS failed to facilitate wakeful consolidation, suggesting that alpha entrainment alone was not the facilitative mechanism. Using neuroimaging of multiple modalities, we observed augmented event-related potential and heightened neural excitation in the early visual cortex after 10-Hz grating-form RVS, implying an involvement of long-term potentiation-like (LTP-like) plasticity. Collectively, we provide a new photic method for modulating the offline processing of encoded sensory information and suggest a role of sensory tetanization in the modulation.
MdLRR-RLK1-MdATG3 module enhances the resistance of apples to abiotic stress via autophagy
Authors: Chen Wenjun , Guo Wei , Zhang Chao , Zhao Yi , Lei Yingying , Chen Cui , Wei Ziwen , Dai Hongyan
Published: September 2024

LRR-RLKs play a key role in plant responses to stress, although their physiological functions under abiotic stress are not yet fully understood.MdLRR-RLK1was found to regulate plant growth and development and to increase tolerance to salt and drought stress. MdLRR-RLK1 interacts with MdATG3, which ubiquitinates and degrades MdLRR-RLK1. MdATG3 enhances salt and drought tolerance through autophagy, interacting with MdATG8F/I-like in apple. These findings reveal the interaction between MdLRR-RLK1 and MdATG3, suggesting mechanisms that regulate apple growth and resistance to abiotic stress.
Efficiency metrics for performance measurement: a review in higher education of main methods and determinants
Authors: Rella Angela , Vitolla Filippo
Published: September 2024

Purpose

This study aims to provide an overview of the state-of-the-art in efficiency measurement within higher education (HE). Specifically, it seeks to gather all relevant articles on the topic and subsequently categorize these studies using a flowchart based on two core aspects of the topic.

Design/methodology/approach

This study employs bibliometric and content analyses to conduct a systematic literature review. The Preferred Reporting Items for Systematic Review (PRISMA) framework is used to identify the search protocol, followed by analyses to classify and categorize articles.

Findings

The bibliometric analysis identifies prominent themes, methodologies and literature gaps. The content findings highlight key insights on higher educational institution (HEI) efficiency, including organizational structures, services and operational activities.

Originality/value

This research contributes to the existing knowledge by synthesizing global literature on HEI’s efficiency. Utilizing the flowchart developed by the authors, the study captures the state-of-the-art based on two critical aspects: methodologies and content. Insights from the analysis and subsequent classification of previous literature provide valuable directions for future research.
Does board ethnic diversity affect IFRS disclosures?
Authors: Tawiah Vincent Konadu , Gyapong Ernest , Wang Yan
Published: September 2024

Purpose

This paper examines the impact of board ethnic diversity on the level of compliance with international financial reporting standards (IFRS) disclosures.

Design/methodology/approach

Using a unique hand-collected dataset from South Africa, we develop a comprehensive disclosure index against 570 mandatory requirements of IFRS. Further, we employ the fixed-effects model to investigate whether board ethnic diversity affects IFRS disclosures.

Findings

We document a significant positive association between ethnic minority directors and IFRS disclosure levels. Furthermore, we reveal that non-busy ethnic minority directors have a greater impact on IFRS disclosure levels than their busy counterparts. Additional analyses show that ethnic minority directors have less impact on IFRS disclosure levels when their number exceeds two. Companies with more ethnic directors on audit committees are more likely to comply with IFRS disclosure requirements and ethnic diversity increases accounting disclosures irrespective of the level of ownership concentration.

Originality/value

Our findings shed new light on the impact of board ethnic diversity on firms’ compliance with IFRS disclosure requirements. The results are robust to alternative econometric techniques, proxies and potential endogeneity concerns.