bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiplane HiLo microscopy with speckle illumination and non-local means denoising
Authors: Zheng Shuqi , Koyama Minoru , Mertz Jerome 
Published: September 2023

AbstractSignificanceHiLo microscopy synthesizes an optically-sectioned image from two images, one obtained with uniform and another with patterned illumination, such as laser speckle. Speckle-based HiLo has the advantage of being robust to aberrations, but is susceptible to residual speckle noise that is difficult to control. We present a computational method to reduce this residual noise without compromising spatial resolution. In addition, we improve the versatility of HiLo microscopy by enabling simultaneous multiplane imaging (here 9 planes).AimOur goal is to perform fast, high contrast multiplane imaging with a conventional camera-based fluorescence microscope.ApproachMultiplane HiLo imaging is achieved with the use of a single camera and z-splitter prism. Speckle noise reduction is based on the application of a non-local means (NLM) denoising method to perform ensemble averaging of speckle grains.ResultsWe demonstrate the capabilities of multiplane HiLo with NLM denoising both with synthesized data and by imaging cardiac and brain activity in zebrafish larvae at 40 Hz frame rates.ConclusionsMultiplane HiLo microscopy aided by NLM denoising provides a simple tool for fast, opticallysectioned volumetric imaging that can be of general utility for fluorescence imaging applications.
An actomyosin network organizes niche morphology and responds to feedback from recruited stem cells
Authors: Warder Bailey N. , Nelson Kara A. , Sui Justin , Anllo Lauren , DiNardo Stephen 
Published: September 2023

SummaryStem cells often rely on signals from a niche, which in many tissues adopts a precise morphology. What remains elusive is how niches are formed, and how morphology impacts function. To address this, we leverage theDrosophilagonadal niche, which affords genetic tractability and live-imaging. We have previously shown mechanisms dictating niche cell migration to their appropriate position within the gonad, and the resultant consequences on niche function. Here, we show that once positioned, niche cells robustly polarize filamentous actin (F-actin) and Non-muscle Myosin II (MyoII) towards neighboring germ cells. Actomyosin tension along the niche periphery generates a highly reproducible smoothened contour. Without contractility, niches are misshapen and exhibit defects in their ability to regulate germline stem cell behavior. We additionally show that germ cells aid in polarizing MyoII within niche cells, and that extrinsic input is required for niche morphogenesis and function. Our work reveals a feedback mechanism where stem cells shape the niche that guides their behavior.
Identification of functional white matter networks in BOLD fMRI
Authors: Eby Alexa L. , Remedios Lucas W. , Kim Michael E. , Li Muwei , Gao Yurui , Gore John C. , Schilling Kurt G. , Landman Bennett A. 
Published: September 2023

ABSTRACTWhite matter signals in resting state blood oxygen level dependent functional magnetic resonance (BOLD-fMRI) have been largely discounted, yet there is growing evidence that these signals are indicative of brain activity. Understanding how these white matter signals capture function can provide insight into brain physiology. Moreover, functional signals could potentially be used as early markers for neurological changes, such as in Alzheimer’s Disease. To investigate white matter brain networks, we leveraged the OASIS-3 dataset to extract white matter signals from resting state BOLD-FMRI data on 711 subjects. The imaging was longitudinal with a total of 2,026 images. Hierarchical clustering was performed to investigate clusters of voxel-level correlations on the timeseries data. The stability of clusters was measured with the average Dice coefficients on two different cross fold validations. The first validated the stability between scans, and the second validated the stability between subject populations. Functional clusters at hierarchical levels 4, 9, 13, 18, and 24 had local maximum stability, suggesting better clustered white matter. In comparison with JHU-DTI-SS Type-I Atlas defined regions, clusters at lower hierarchical levels identified well defined anatomical lobes. At higher hierarchical levels, functional clusters mapped motor and memory functional regions, identifying 50.00%, 20.00%, 27.27%, and 35.14% of the frontal, occipital, parietal, and temporal lobe regions respectively.
Microglial 25-hydroxycholesterol mediates neuroinflammation and neurodegeneration in a tauopathy mouse model
Authors: Toral-Rios Danira , Long Justin M , Ulrich Jason D. , Yu Jinsheng , Strickland Michael R. , Han Xianlin , Holtzman David M , Cashikar Anil G , Paul Steven M 
Published: September 2023

ABSTRACTAlzheimer’s disease (AD) is characterized by amyloid plaques and neurofibrillary tangles in addition to neuroinflammation and changes in brain lipid metabolism. Recent findings have demonstrated that microglia are key drivers of neurodegeneration in tauopathy mouse models. A subset of microglia referred to as disease-associated microglia (DAM) display gene signatures signifying changes in proinflammatory signaling and lipid metabolism in mouse models of amyloid and tau pathology.Ch25his a DAM gene encoding cholesterol 25-hydroxylase that produces 25-hydroxycholesterol (25HC), a known modulator of inflammation as well as lipid metabolism. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown. Here, we show that in the absence of Ch25h and the resultant reduction in 25HC there is strikingly reduced age-dependent neurodegeneration and neuroinflammation in the hippocampus and entorhinal/piriform cortex of PS19 mice, which express the P301S mutant human tau transgene. Transcriptomic analyses of bulk hippocampal tissue and single nuclei revealed that Ch25h deficiency in PS19 mice strongly suppressed proinflammatory cytokine and chemokine signaling in microglia and restored sterol synthesis. Our results suggest a key role for Ch25h/25HC in potentiating proinflammatory signaling to promote tau-mediated neurodegeneration. Ch25h may represent a novel therapeutic target for primary tauopathies, AD, and other neuroinflammatory diseases.
Representational similarity supports rapid context retrieval during fear discrimination in ventral hippocampus
Authors: Rozeske Robert R. , Runtz Léonie , Keinath Alexandra T. , Sossin Aaron , Brandon Mark P. 
Published: September 2023

SummaryThe dorsal and ventral regions of the hippocampus (dCA1 and vCA1) are critical for contextual fear conditioning tasks, yet the dynamics of hippocampal neuronal representations during memory acquisition, retrieval, and extinction processes have yet to be fully elucidated. The canonical theory is that the hippocampus generates and retrieves spatial maps of contexts during memory acquisition and retrieval. It is hypothesized the hippocampus prevents memory interference by generating context representations that are dissimilar and the prediction follows that representation dissimilarity facilitates discrimination between contexts. Here, we developed a context fear memory retrieval task and combined it with 1-photon neuronal imaging in dCA1 and vCA1 of freely behaving mice to test this prediction. We identified several phenomena specific to vCA1. First, fear conditioning induced an immediate and strong representational change that was predictive of freezing behavior. During context discrimination, vCA1 representations of the threatening and neutral contexts became more similar. Third, during threatening context memory retrieval, vCA1 expressed rapid and strong context representations. These unexpected results suggest that representational similarity in vCA1 facilitates faster and more efficient network state transitions. In further support of this view, both phenomena of representational similarity and rapid context recall were no longer observed in vCA1 once fear behavior was extinguished. Together, these results reveal that vCA1 unexpectedly generates similar population codes, promoting faster transitions between network states essential for contextual fear memory retrieval.HighlightsWe established a novel context teleportation task that allows population level hippocampal recordings during key moments of threat memory acquisition, retrieval, and extinction.The ventral region of CA1 (vCA1) exhibited the greatest change in neural representation during fear memory acquisition, compared to dorsal CA1 (dCA1).After fear conditioning, representations for threatening and neutral contexts were more similar in vCA1 compared to dCA1, yet representational similarity in vCA1 supported rapid context memory retrieval.Context fear memory extinction reversed the context representation in vCA1 to patterns observed prior to fear conditioning.Graphical Abstract
Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes
Authors: Devkota Sujan , Zhou Rui , Nagarajan Vaishnavi , Maesako Masato , Do Hung , Noorani Arshad , Overmeyer Caitlin , Bhattarai Sanjay , Douglas Justin T. , Saraf Anita , Miao Yinglong , Ackley Brian D. , Shi Yigong , Wolfe Michael S. 
Published: September 2023

AbstractAlzheimer’s disease is characterized pathologically by cerebral deposition of 42-residue amyloid β-peptide (Aβ42), proteolytically produced from amyloid precursor protein (APP) by β- and γ-secretases.1Although mutations in APP and presenilin, the catalytic component of γ-secretase, cause familial Alzheimer’s disease (FAD), a role for Aβ42 as the primary disease driver has not been clearly established and remains controversial.2,3Here we show through comprehensive analysis of the multi-step proteolysis of APP substrate C99 by γ-secretase that FAD mutations are consistently deficient in early proteolytic events, not later events that produce secreted Aβ peptides. Cryo-electron microscopy revealed that a substrate mimetic traps γ-secretase at the transition state for intramembrane proteolysis, and this structure closely aligns with activated enzyme-substrate complex captured by molecular dynamics simulations.In silicosimulations and fluorescence lifetime imaging microscopy in cultured cells support stabilization by FAD mutations of enzyme-substrate and/or enzyme-intermediate complexes. Neuronal expression of C99 and/or presenilin-1 inCaenorabditis elegansled to age-dependent synaptic loss only when one of the transgenes carried an FAD mutation. Designed mutations that stabilize the enzyme-substrate complex and block proteolysis likewise led to synaptic loss. Collectively, these findings implicate the stalled process—not the released products—of γ-secretase cleavage of substrates in FAD pathogenesis.
Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to naloxone administration
Authors: Bedard Madigan L. , Murray Jackson G. , Huang Xi-Ping , Nowlan Alexandra C. , Conley Sara Y. , Mott Sarah E. , Loyack Samuel J. , Cline Calista A. , Clodfelter Caroline G. , Dasgupta Nabarun , Roth Bryan L. , McElligott Zoe A. 
Published: September 2023

AbstractXylazine has been found in the unregulated drug supply at increasing rates, usually in combination with fentanyl. It has become critical to understand its basic pharmacology, how it impacts behavior, and how it interacts with fentanyl in rodent models of opioid administration. Despite commentary from scientists, politicians, and public health officials, it is not known if xylazine impacts the efficacy of naloxone, the opioid receptor antagonist used to reverse opioid induced respiratory depression. Furthermore, few studies have examined the effects of xylazine alone, without co-administration of ketamine. Here, we examine the impact of xylazine alone and in combination with fentanyl on several key behaviors in male and female mice. We demonstrate differential locomotor responses by dose and sex to xylazine. Surprisingly, our results further indicate that naloxone precipitates withdrawal from xylazine and a fentanyl/xylazine combination, in both sexes, with enhanced sensitivity in females. Further, we show that xylazine is a full agonist at the kappa opioid receptor, a potential mechanism for its naloxone sensitivity.One-Sentence SummaryWe present surprising new insights into xylazine and fentanyl pharmacology with immediate implications for clinical practice and frontline public health.
Unveiling a Novel Memory Center in Humans: Neurochemical Identification of theNucleus Incertus, a Key Pontine Locus Implicated in Stress and Neuropathology
Authors: Ávila Camila de , Gugula Anna , Trenk Aleksandra , Intorcia Anthony J. , Suazo Crystal , Nolz Jennifer , Plamondon Julie , Khatri Divyanshi , Tallant Lauren , Caron Alexandre , Błasiak Anna , Serrano Geidy E. , Beach Thomas G. , Gundlach Andrew L. , Mastroeni Diego F. 
Published: September 2023

AbstractBackgroundThenucleus incertus(NI) was originally described by Streeter in 1903, as a midline region in the floor of the fourth ventricle (4V) of the human brain with an ‘unknown’ function. More than a century later, the neuroanatomy of the NI including its forebrain target regions has been described in lower vertebrates, but not in humans. Therefore, we examined the neurochemical anatomy of the human NI using several markers, including the neuropeptide, relaxin-3 (RLN3), and began to explore the distribution of the NI-related RLN3 innervation of the hippocampus.MethodsHistochemical staining of serial, coronal sections (30 µm) of control human postmortem pons was conducted to reveal the presence of the NI by detection of immunoreactivity (IR) for the neuronal marker, microtubule-associated protein-2 (MAP2), two markers present in rat NI, glutamic acid dehydrogenase (GAD)-65/67 and corticotrophin releasing hormone receptor 1 (CRHR1), and RLN3, which is highly expressed in a major population of NI neurons in diverse species.RLN3and vesicular GABA transporter 1 (vGAT1) mRNA was detected by multiplex, fluorescence in situ hybridization. Postmortem pons sections containing the NI from an Alzheimer’s disease (AD) case were immunostained for phosphorylated-tau (AT8 antibody), to explore potential relevance to neurodegenerative diseases. Lastly, sections of human hippocampus were stained to detect RLN3-IR and somatostatin (SST)-IR, as SST is expressed in interneurons targeted by RLN3 projections in rodents.ResultsIn the dorsal, anterior-medial region of the human pons, neurons containing RLN3– and MAP2-IR, andRLN3/vGAT1mRNA-positive neurons were observed in an anatomical pattern consistent with that of the NI in other species. GAD65/67– and CRHR1-immunopositive neurons were also detected within this area. Furthermore, RLN3– and AT8-IR were co-localized within NI neurons of an AD subject. Lastly, RLN3-IR was detected in neurons within the CA1, CA2, CA3, and DG areas of the hippocampus, in the absence ofRLN3mRNA. In the DG, RLN3– and SST-IR were co-localized in a small population of neurons.ConclusionsAspects of the anatomy of the human NI are shared across species, including a population of RLN3-expressing neurons and a RLN3 innervation of the hippocampus. Accumulation of phosphorylated-tau in the NI suggests its possible involvement in AD pathology. Further characterization of the neurochemistry of the human NI will increase our understanding of its functional role in health and disease.Graphical AbstractCreated with BioRender.com
Context-dependent decision-making in the primate hippocampal-prefrontal circuit
Authors: Elston Thomas W. , Wallis Joni D. 
Published: September 2023

AbstractWhat is good in one scenario might be bad in another. Despite the ubiquity of such contextual reasoning in everyday choice, how the brain flexibly utilizes different valuation schemes across contexts remains unknown. We addressed this question by monitoring neural activity from the hippocampus (HPC) and orbitofrontal cortex (OFC) of two monkeys performing a state-dependent choice task. We found that HPC neurons encoded state information as it became available and then, at the time of choice, relayed this information to OFC via theta synchronization. During choice, OFC represented value in a state-dependent manner: many OFC neurons uniquely coded for value in only one state but not the other. This suggests a functional dissociation whereby HPC encodes contextual information that is broadcast to OFC via theta synchronization to select a state-appropriate value subcircuit, thus allowing for contextual reasoning in value-based choice.
An adapted stem cell-derived microglia protocol for the study of microgliopathies and other neurological disorders
Authors: Dorion Marie-France , Casas Diana , Yaqubi Moein , Fleming Peter , Chen Carol X.-Q. , Piscopo Valerio E. C. , Nicouleau Michael , Goldsmith Taylor M. , Shlaifer Irina , MacDonald Adam , Dudley Roy W. R. , Hall Jeffrey A. , Antel Jack P. , Stratton Jo Anne , Durcan Thomas M. , Piana Roberta La , Healy Luke M. 
Published: September 2023

AbstractBackgroundAdult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a primary microgliopathy caused by pathogenic variants in the colony-stimulating factor 1 receptor (CSF1R) gene. Since CSF1R signaling is crucial for microglia development, survival and function, induced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial defects caused by ALSP patient-specificCSF1Rvariants.MethodsSerial modifications to an existing iMGL protocol were made, including but not limited to changes in growth factor combination to drive microglial differentiation, until successful derivation of microglia-like cells from an ALSP patient carrying a c.2350G > A (p.V784M)CSF1Rvariant. Using healthy control lines, the quality of the new iMGL protocol was validated through cell yield assessment, measurement of microglia marker expression, transcriptomic comparison to primary microglia, and evaluation of inflammatory and phagocytic activities. Similarly, molecular and functional characterization of the ALSP patient-derived iMGL was carried out in comparison to healthy control iMGL.ResultsThe newly devised protocol allowed the generation of iMGL with enhanced transcriptomic similarity to primary human microglia and with higher phagocytic and inflammatory competence at ∼3-fold greater yield compared to the original protocol. Using this protocol, decreased CSF1R autophosphorylation and cell surface expression was observed in iMGL derived from the ALSP patient compared to those derived from healthy controls. Additionally, ALSP patient-derived iMGL presented a migratory defect accompanying a temporal reduction in purinergic receptor P2Y12 (P2RY12) expression. Finally, ALSP patient-derived cells showed surprisingly high phagocytic capacity, which was associated with higher lysosomal content.ConclusionsWe optimized a pre-existing iMGL protocol, generating a powerful tool to study microglial involvement in human neurological diseases. Using the optimized protocol, we have generated for the first time iMGL from an ALSP patient carrying a pathogenicCSF1Rvariant, with preliminary characterization pointing toward functional alterations in migratory and phagocytic activities.
SignEEG v1.0 : Multimodal Dataset with Electroencephalography and Hand-written Signature for Biometric Systems
Authors: Mishra Ashish Ranjan , Kumar Rakesh , Gupta Vibha , Prabhu Sameer , Upadhyay Richa , Chhipa Prakash Chandra , Rakesh Sumit , Mokayed Hamam , Chakladar Debashis Das , De Kanjar , Liwicki Marcus , Liwicki Foteini Simistira , Saini Rajkumar 
Published: September 2023

ABSTRACTHandwritten signatures in biometric authentication leverage unique individual characteristics for identification, offering high specificity through dynamic and static properties. However, this modality faces significant challenges from sophisticated forgery attempts, underscoring the need for enhanced security measures in common applications. To address forgery in signature-based biometric systems, integrating a forgery-resistant modality, namely, noninvasive electroencephalography (EEG), which captures unique brain activity patterns, can significantly enhance system robustness by leveraging multimodality’s strengths. By combining EEG, a physiological modality, with handwritten signatures, a behavioral modality, our approach capitalizes on the strengths of both, significantly fortifying the robustness of biometric systems through this multimodal integration. In addition, EEG’s resistance to replication offers a high-security level, making it a robust addition to user identification and verification. This study presents a new multimodalSignEEG v1.0dataset based on EEG and hand-drawn signatures from 70 subjects. EEG signals and hand-drawn signatures have been collected withEmotiv InsightandWacom Onesensors, respectively. The multimodal data consists of three paradigms based on mental, & motor imagery, and physical execution: i) thinking of the signaturés image, (ii) drawing the signature mentally, and (iii) drawing a signature physically. Extensive experiments have been conducted to establish a baseline with machine learning classifiers. The results demonstrate that multimodality in biometric systems significantly enhances robustness, achieving high reliability even with limited sample sizes. We release the raw, pre-processed data and easy-to-follow implementation details.
Structure-based discovery of CFTR potentiators and inhibitors
Authors: Liu Fangyu , Kaplan Anat Levit , Levring Jesper , Einsiedel Jürgen , Tiedt Stephanie , Distler Katharina , Omattage Natalie S. , Kondratov Ivan S. , Moroz Yurii S. , Pietz Harlan L. , Irwin John J. , Gmeiner Peter , Shoichet Brian K. , Chen Jue 
Published: September 2023

AbstractThe cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, while its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify novel CFTR modulators. We docked ∼155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered novel mid-nanomolar potentiators as well as inhibitors that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.