bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACTLipids 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.HIGHLIGHTSLipid droplets (LD) normally form in neurons across species Neuronal LD are regulated by a conserved gene networkNeuronal LD regulation plays a conserved and sex-biased role in maintaining energy homeostasisLD regulation supports ER and mitochondrial function in hunger-activated neuronsGRAPHICAL 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

AbstractThe 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 NoteworthyWith 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

AbstractPurposeHigh-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.MethodsWe 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.ResultsResults 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.ConclusionThis 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

AbstractParkinson’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

AbstractUltrasound 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

AbstractAs 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.
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

AbstractCognitive 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

AbstractIn 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.
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

AbstractMulti-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

AbstractThe 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

AbstractExercise 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

ABSTRACTExtracellular 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.