bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spike Protein NTD mutation G142D in SARS-CoV-2 Delta VOC lineages is associated with frequent back mutations, increased viral loads, and immune evasion
Authors: Shen Lishuang , Triche Timothy J. , Bard Jennifer Dien , Biegel Jaclyn A. , Judkins Alexander R. , Gai Xiaowu 
Published: September 2021

AbstractThe significantly greater infectivity of the SARS-CoV-2 Delta variants of concern (VOC) is hypothesized to be driven by key mutations that result in increased transmissibility, viral load and/or evasion of host immune response. We surveyed the mutational profiles of Delta VOC genomes between September 2020 and mid-August 2021 and identified a previously unreported mutation pattern at amino acid position 142 in the N-terminal domain (NTD) of the spike protein which demonstrated multiple rounds of mutation from G142 to D142 and back. This pattern of frequent back mutations was observed at multiple time points and across Delta VOC sub-lineages. The etiology for these recurrent mutations is unclear but raises the possibility of host-directed editing of the SARS-CoV-2 genome. Within Delta VOC this mutation is associated with higher viral load, further enhanced in the presence of another NTD mutation (T95I) which was also frequently observed in these cases. Protein modeling of both mutations predicts alterations of the surface topography of the NTD by G142D, specifically disturbance of the ‘super site’ epitope that binds NTD-directed neutralizing antibodies (NAbs). The appearance of frequent and repeated G142D followed by D142G back mutations is previously unreported in SARS-CoV-2 and may represent viral adaptation to evolving host immunity characterized by increasing frequency of spike NAbs, from both prior infection and vaccine-based immunity. The emergence of alterations of the NTD in and around the main NAb epitope is a concerning development in the ongoing evolution of SARS-CoV-2 which may contribute to increased infectivity, immune evasion and ‘breakthrough infections’ characteristic of Delta VOC. Future vaccine and therapy development may benefit by recognizing the emergence of these novel spike NTD mutations and considering their impact on antibody recognition, viral neutralization, infectivity, replication, and viral load.
Refractive-index matching enhanced polarization sensitive optical coherence tomography quantification in human brain tissue
Authors: Liu Chao J. , Ammon William , Jones Robert J. , Nolan Jackson , Wang Ruopeng , Chang Shuaibin , Frosch Matthew P. , Yendiki Anastasia , Boas David A. , Magnain Caroline , Fischl Bruce , Wang Hui 
Published: September 2021

AbstractThe importance of polarization-sensitive optical coherence tomography (PS-OCT) has been increasingly recognized in human brain imaging. Despite the recent progress of PS-OCT in revealing white matter architecture and orientation, quantification of fine-scale fiber tracts in the human brain cortex has been a challenging problem, due to a low birefringence in the gray matter. In this study, we investigated the effect of refractive index matching by 2,2’-thiodiethanol (TDE) immersion on the improvement of PS-OCT measurements inex vivohuman brain tissue. We obtain the cortical fiber orientation maps in the gray matter, which reveals the radial fibers in the gyrus, the U-fibers along the sulcus, as well as distinct layers of fiber axes exhibiting laminar organization. Further analysis shows that index matching reduces the noise in axis orientation measurements by 56% and 39%, in white and gray matter, respectively. Index matching also enables precise measurements of apparent birefringence, which was underestimated in the white matter by 82% but overestimated in the gray matter by 16% prior to TDE immersion. Mathematical simulations show that the improvements are primarily attributed to the reduction in the tissue scattering coefficient, leading to an enhanced signal-to-noise ratio in deeper tissue regions, which could not be achieved by conventional noise reduction methods.
Addiction-Related Memory Transfer and Retention in Planaria
Authors: Samuel Kenneth , Suviseshamuthu Easter S. , Fichera Maria E. 
Published: September 2021

AbstractMemory retention and transfer in organisms happen at either the neural or genetic level. In humans, addictive behavior is known to pass from parents to offspring. In flatworm planaria (Dugesia tigrina), memory transfer has been claimed to be horizontal, i.e., through cannibalism. Our study is a preliminary step to understand the mechanisms underlying the transfer of addictive behavior to offspring. Since the neural and neurochemical responses of planaria share similarities with humans, it is possible to induce addictions and get predictable behavioral responses. Addiction can be induced in planaria, and decapitation will reveal if the addictive memories are solely stored in the brain. The primary objective was to test the hypothesis that addictive memory is also retained in the brainless posterior region of planaria. The surface preference of the planaria was first determined between smooth and rough surfaces. Through Pavlovian conditioning, the preferred surface was paired with water and the unpreferred surface with sucrose. After the planaria were trained and addicted, their surface preference shifted as a conditioned place preference (CPP) was established. When decapitated, the regenerated segment from the anterior part containing the brain retained the addiction, thus maintaining a shift in the surface preference. Importantly, we observed that the posterior part preserved this CPP as well, suggesting that memory retention is not attributed exclusively to the brain but might also occur at the genetic level. As a secondary objective, the effects of neurotransmitter blocking agents in preventing addiction were studied by administering a D1 dopamine antagonist to planaria, which could provide pointers to treat addictions in humans.
Methylphenidate as a causal test of translational and basic neural coding hypotheses
Authors: Ni Amy M. , Bowes Brittany S. , Ruff Douglas A. , Cohen Marlene R. 
Published: September 2021

SUMMARYMost systems neuroscience studies fall into one of two categories: basic science work aimed at understanding the relationship between neurons and behavior, or translational work aimed at developing treatments for neuropsychiatric disorders. Here we use these two approaches to inform and enhance each other. Our study both tests hypotheses about basic science neural coding principles and elucidates the neuronal mechanisms underlying new, clinically relevant behavioral effects of systemically administered methylphenidate (Ritalin). We discovered that orally administered methylphenidate, used clinically to treat Attention Deficit Hyperactivity Disorder (ADHD) and generally to enhance cognition (Lakhan & Kirchgessner, 2012; Maher, 2008), increases spatially selective visual attention, enhancing visual performance at only the attended location. And as predicted by our previous work (Ni et al., 2018), we found that this causal manipulation enhances vision in rhesus macaques specifically when it decreases the mean correlated variability of neurons in visual area V4. Our findings demonstrate that the visual system is a platform for understanding the neural underpinnings of both complex cognitive processes (basic science) and neuropsychiatric disorders (translation). Addressing basic science hypotheses, our results are consistent with a scenario in which methylphenidate has cognitively specific effects by working through naturally selective cognitive mechanisms. Clinically, our findings suggest that the often staggeringly specific symptoms of neuropsychiatric disorders may be caused and treated by leveraging general mechanisms.
Persistent oxidative stress and inflammasome activation in CD14highCD16-monocytes from COVID-19 patients
Authors: Lage Silvia Lucena , Amaral Eduardo Pinheiro , Hilligan Kerry L. , Laidlaw Elizabeth , Rupert Adam , Namasivayan Sivaranjani , Rocco Joseph , Galindo Frances , Kellogg Anela , Kumar Princy , Poon Rita , Wortmann Glenn W. , Shannon John P. , Hickman Heather D. , Lisco Andrea , Manion Maura , Sher Alan , Sereti Irini 
Published: September 2021

ABSTRACTThe poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome and oxidative stress have independently been implicated in COVID-19, it is poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment of CD14highCD16-monocytes displaying inflammasome activation evidenced by caspase-1/ASC-speck formation in severe COVID-19 patients when compared to mild ones and healthy controls, respectively. Those cells also showed aberrant levels of mitochondrial superoxide (MitoSOX) and lipid peroxidation, both hallmarks of the oxidative stress response, which strongly correlated with caspase-1 activity. In addition, we found that NLRP3 inflammasome-derived IL-1β secretion by SARS-CoV-2- exposed monocytesin vitrowas partially dependent on lipid peroxidation. Importantly, altered inflammasome and stress responses persisted after short- term patient recovery. Collectively, our findings suggest oxidative stress/NLRP3 signaling pathway as a potential target for host-directed therapy to mitigate early COVID-19 hyperinflammation as well as its long-term outcomes.
Severe Acute Respiratory Syndrome Coronavirus-2 seropositivity in South-Central Uganda, during 2019 - 2021
Authors: Ssuuna Charles , Galiwango Ronald Moses , Kankaka Edward Nelson , Kagaayi Joseph , Ndyanabo Anthony , Kigozi Godfrey , Nakigozi Gertrude , Lutalo Tom , Ssekubugu Robert , Wasswa John Bosco , Mayinja Anthony , Nakibuuka Martina Cathy , Jamiru Samiri , Oketch John Baptist , Muwanga Edward , Chang Larry William , Grabowski Mary Kate , Wawer Maria , Gray Ronald , Anderson Mark , Stec Michael , Cloherty Gavin , Laeyendecker Oliver , Reynolds Steven James , Quinn Thomas C. , Serwadda David 
Published: September 2021

AbstractGlobally, key subpopulations have a high risk of contracting SARS-CoV-2. In Uganda, limited access to personal protective equipment amidst lack of clarity on the extent of the community disease burden may exacerbate this situation.We assessed SARS-CoV-2 antibody seroprevalence among high-risk sub-populations, including healthcare workers, persons within the general population previously reporting experiencing key COVID-19 like symptoms and archived plasma specimens collected prior to confirmation of COVID-19 in Uganda.We collected venous blood from HCWs at selected health facilities and from population-cohort participants who reported specific COVID-19 like symptoms in a prior phone-based survey conducted during the first national lockdown (May-August 2020). Pre-lockdown plasma collected from individuals considered high risk for SARS-CoV-2 infection was retrieved. Specimens were tested for antibodies to SARS-CoV-2 using the CoronaChek™ rapid COVID-19 IgM/IgG lateral flow test assay. IgM only positive samples were confirmed using a chemiluminescent microparticle immunoassay (ARCHITECT AdviseDx SARS-CoV-2 IgM) which targets the spike. SARS-CoV-2 exposure was defined as either confirmed IgM, both IgM and IgG or sole IgG positivity.The seroprevalence of antibodies to SARS-CoV-2 in HCWs was 21.1% [95%CI: 18.2-24.2]. Of the phone-based survey participants, 11.9% [95%CI: 8.0-16.8] had antibodies to SARS-CoV-2. Among 636 pre-lockdown plasma specimens, 1.7% [95%CI: 0.9-3.1] were reactive.Findings suggest a high seroprevalence of antibodies to SARS-CoV-2 among HCWs and substantial exposure in persons presenting with specific COVID-19 like symptoms in the general population of South-central Uganda. Based on current limitations in serological test confirmation, it remains unclear whether pre-lockdown seropositivity implies prior SARS-CoV-2 exposure in Uganda.
Adaptation and serial choice bias are unaltered in autism
Authors: Bosch Ella , Fritsche Matthias , Utzerath Christian , Buitelaar Jan K. , de Lange Floris P 
Published: September 2021

AbstractAutism Spectrum Disorder (ASD) or autism is characterized by social and non-social symptoms, including sensory hyper- and hyposensitivities. A suggestion has been put forward that some of these symptoms could be explained by differences in how sensory information is integrated with its context, including a lower tendency to leverage the past in the processing of new perceptual input. At least two history-dependent effects of opposite directions have been described in the visual perception literature: a repulsive adaptation effect, where perception of a stimulus is biased away from an adaptor stimulus, and an attractive serial choice bias, where perceptual choices are biased towards the previous choice. In this study, we investigated whether autistic participants differed in either bias from typically developing controls (TD). Sixty-four adolescent participants (31 with ASD, 33 TD) were asked to categorize oriented line stimuli in two tasks which were designed so that we would induce either adaptation or serial choice bias. Although our tasks successfully induced both biases, in comparing the two groups, we found no differences in the magnitude of adaptation nor in the modulation of perceptual choices by the previous choice. In conclusion, we find no evidence of a decreased integration of the past in visual perception of autistic individuals.
c-Kit mediates cutaneous sensory axon innervation and multi-kinase inhibitor-induced neurotoxicity
Authors: Tuttle Adam M. , Pomaville Matthew B. , Delgado Katherine C. , Wright Kevin M. , Nechiporuk Alex V. 
Published: September 2021

ABSTRACTPeripheral somatosensory neurons innervate the skin and sense the environment. Loss of skin innervation, often caused by the “dying back” of distal somatosensory axons, is a common side effect of drug-induced peripheral neuropathies (DIPNs) and results in pain and sensory dysfunction. Targeted cancer therapies frequently employ multi-kinase inhibitor (MKI) drugs that each block multiple receptor tyrosine kinases. Many MKIs produce DIPNs but the molecular targets and cellular mechanisms underlying these are unknown. We performed live-imaging of cutaneous somatosensory axons in larval zebrafish during treatment with several MKIs known to induce DIPNs, and observed axonal retraction consistent with a dying back pathology. These results were replicated in mouse somatosensory neurons. Genetic knockout of potential MKI targets identified c-Kit receptor as a regulator of sensory axon innervation and a major target of these MKIs mediating loss of axonal density. In both fish and mammals, Kit receptor is expressed in cutaneous somatosensory neurons and its ligand, Kitlg, is expressed in the skin. Mosaic misexpression of Kitlg in the skin induced dramatic increases in local sensory axon density, suggesting an important role for Kit signaling in cutaneous axon growth and maintenance. Immunostaining and structure-function analysis revealed Src, a downstream Kit target, mediates Kit’s role in cutaneous axon innervation and MKI neurotoxicity. Our data shows that the Kit-Src signaling pathway has a major role in cutaneous sensory axon innervation and is a potential therapeutic target to address DIPNs caused by MKIs and other compounds.
RUNIMC: An R-based package for imaging mass cytometry data analysis and pipeline validation
Authors: Dolcetti Luigi , Barber Paul R , Weitsman Gregory , Thavaraj Selvam , Ng Kenrick , Chan Julie Nuo En , Patten Piers , Mustapha Rami , Deng Jinhai , Ng Tony 
Published: September 2021

ABSTRACTWe propose a novel pipeline for the analysis of imaging mass cytometry data, comparing an unbiased approach, representing the actual gold standard, with a novel biased method. We made use of both synthetic/ controlled datasets as well as two datasets obtained from FFPE sections of follicular lymphoma, and head and neck patients, stained with a 14 and 29-markers panels respectively. The novel pipeline, denominated RUNIMC, has been completely developed in R and contained in a single package. The novelty resides in the ease with which multi-class random forest classifier can be used to classify image features, making the pathologist’s and expert classification pivotal, and the use of a random forest regression approach that permits a better detection of cell boundaries, and alleviates the necessity of relying on a perfect nuclear staining.
Gli1 regulates the postnatal acquisition of peripheral nerve architecture
Authors: Zotter Brendan , Dagan Or , Brady Jacob , Baloui Hasna , Samanta Jayshree , Salzer James L. 
Published: September 2021

ABSTRACTPeripheral nerves are organized into discrete cellular compartments. Axons, Schwann cells (SCs), and endoneurial fibroblasts (EFs) reside within the endoneurium and are surrounded by the perineurium - a cellular sheath comprised of layers of perineurial glia (PNG). SC secretion of Desert Hedgehog (Dhh) regulates this organization. In Dhh nulls, the perineurium is deficient and the endoneurium is subdivided into small compartments termed minifascicles. Human Dhh mutations cause a peripheral neuropathy with similar defects. Here we examine the role of Gli1, a canonical transcriptional effector of hedgehog signaling, in regulating peripheral nerve organization. We identify PNG, EFs, and pericytes as Gli1-expressing cells by genetic fate mapping. Although expression of Dhh by SCs and Gli1 in target cells is coordinately regulated with myelination, Gli1 expression unexpectedly persists in Dhh null EFs. Thus, Gli1 is expressed in EFs non-canonically i.e., independent of hedgehog signaling. Gli1 and Dhh also have non-redundant activities. In contrast to Dhh nulls, Gli1 nulls have a normal perineurium. Like Dhh nulls, Gli1 nulls form minifascicles, which we show likely arise from EFs. Thus, Dhh and Gli1 are independent signals: Gli1 is dispensable for perineurial development but functions cooperatively with Dhh to drive normal endoneurial development. During development, Gli1 also regulates endoneurial extracellular matrix production, nerve vascular organization, and has modest, non-autonomous effects on SC sorting and myelination of axons. Finally, in adult nerves, induced deletion of Gli1 is sufficient to drive minifascicle formation. Thus, Gli1 regulates the development and is required to maintain the endoneurial architecture of peripheral nerves.SIGNIFICANCE STATEMENTPeripheral nerves are organized into distinct cellular/ECM compartments: the epineurium, perineurium and endoneurium. This organization, with its associated cellular constituents, are critical for the structural and metabolic support of nerves and their response to injury. Here, we show Gli1 - a transcription factor normally expressed downstream of hedgehog signaling - is required for the proper organization of the endoneurium but not the perineurium. Unexpectedly, Gli1 expression by endoneurial cells is independent of, and functions non-redundantly with, Schwann Cell-derived Desert Hedgehog in regulating peripheral nerve architecture. These results further delineate how peripheral nerves acquire their distinctive organization during normal development and highlight mechanisms that may regulate their reorganization in pathologic settings including peripheral neuropathies and nerve injury.
AAV-PHP.S-mediated delivery of reporters to cranial ganglion sensory neurons
Authors: Asencor Andoni I. , Dvoryanchikov Gennady , Tsoulfas Pantelis , Chaudhari Nirupa 
Published: September 2021

ABSTRACTBecause of their ease of use and low risk containment, Adeno-Associated Virus vectors are indispensable tools for much of neuroscience. Yet AAVs have been used relatively little to study the identities and connectivity of peripheral sensory neurons because methods to selectively target particular receptive fields or neuron types have been limited. The introduction of the AAV-PHP.S capsid with selective tropism for peripheral neurons (Chan et al., 2017) offered a solution, which we further elaborate here. We demonstrate using AAV-PHP.S with GFP or mScarlet reporters, that all cranial sensory ganglia, i.e. for cranial nerves V, VII, IX and X, are targeted. Pseudounipolar neurons of both somatic and visceral origin, but not satellite glia, are efficiently transduced rapidly and express the gene of interest within 1 week of injection. Fluorescent reporter proteins are transported into the central and peripheral axons of these sensory neurons, permitting visualization of terminals at high resolution, and/or in intact, cleared brain using light sheet microscopy. By combining a Cre-dependent reporter with the AAV-PHP.S capsid, we confirmed expression in a cell-type dependent manner for both anatomical and targeted functional analyses. The AAV-PHP.S capsid will be a powerful tool for mapping the receptive fields and circuits of molecular subtypes of many somatosensory, gustatory and visceral sensory neurons.SIGNIFICANCE STATEMENTAAV vectors have become an essential tool for visualizing, manipulating, and recoding from neurons of the central nervous system. However, the technology is not widely used for peripheral neurons because of several technical limitations. The AAV-PHP.S synthetic capsid, which targets peripheral neurons, was recently introduced (Chan et al., 2017). Here, we establish key parameters for using this virus, including which cells are transduced, the timing of expression in central and peripheral terminals, distant from neuronal somata, and the effectiveness of Cre-dependent constructs for cell type selective expression. This permits the use of AAV for constructing detailed anatomic and functional maps of the projections of molecular subtypes of peripheral sensory neurons.
MICAL1 activation by PAK1 mediates actin filament disassembly
Authors: McGarry David J. , Castino Giovanni , Lilla Sergio , Zanivan Sara , Olson Michael F. 
Published: September 2021

SummaryThe MICAL1 monooxygenase has emerged as an important regulator of filamentous actin (F-actin) structures that contribute to numerous processes including nervous system development, cell morphology, motility, viability and cytokinesis [1–4]. Activating MICAL1 mutations have been linked with autosomal-dominant lateral temporal epilepsy, a genetic syndrome characterized by focal seizures with auditory symptoms [5], emphasizing the need for tight control of MICAL1 activity. F-actin binding to MICAL1 stimulates catalytic activity, resulting in the oxidation of actin methionine residues that promote F-actin disassembly [6, 7]. Although MICAL1 has been shown to be regulated via interactions of the autoinhibitory carboxyl-terminal coiled-coil region [8] with RAB8, RAB10 and RAB35 GTPases [9–12], or Plexin transmembrane receptors [13, 14], a mechanistic link between the RHO GTPase signaling pathways that control actin cytoskeleton dynamics and the regulation of MICAL1 activity had not been established. Here we show that the CDC42 GTPase effector PAK1 serine/threonine kinase associates with and phosphorylates MICAL1 on serine 817 (Ser817) and 960 (Ser960) residues, leading to accelerated F-actin disassembly. Deletion analysis mapped PAK1 binding to the amino-terminal catalytic monooxygenase and calponin domains, distinct from the carboxyl-terminal proteinprotein interaction domain. Stimulation of cells with extracellular ligands including basic fibroblast growth factor (FGF2) led to significant PAK-dependent Ser960 phosphorylation, thus linking extracellular signals to MICAL1 phosphorylation. Moreover, mass spectrometry analysis revealed that co-expression of MICAL1 with CDC42 and active PAK1 resulted in hundreds of proteins increasing their association with MICAL1, including the previously described MICAL1-interacting protein RAB10 [15]. These results provide the first insight into a redox-mediated actin disassembly pathway linking extracellular signals to cytoskeleton regulation via a RHO GTPase family member, and reveal a novel means of communication between RHO and RAB GTPase signaling pathways.