bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood-brain Barrier Crossing using Magnetic Stimulated Nanoparticles
Authors: Chen Jingfan , Yuan Muzhaozi , Madison Caitlin A , Eitan Shoshana , Wang Ya 
Published: December 2021

ABSTRACTDue to the low permeability and high selectivity of the blood-brain barrier (BBB), existing brain therapeutic technologies are limited by the inefficient BBB crossing of conventional drugs. Magnetic nanoparticles (MNPs) have shown great potential as nano-carriers for efficient BBB crossing under the external static magnetic field (SMF). To quantify the impact of SMF on MNPs’ in vivo dynamics towards BBB crossing, we developed a physiologically based pharmacokinetic (PBPK) model for intraperitoneal (IP) injected superparamagnetic iron oxide nanoparticles coated by gold and conjugated with poly(ethylene glycol) (PEG) (SPIO-Au-PEG NPs) in mice. Unlike most reported PBPK models that ignore brain permeability, we first obtained the brain permeabilities with and without SMF by determining the concentration of SPIO-Au-PEG NPs in the cerebral blood and brain tissue. This concentration in the brain was simulated by the advection-diffusion equations and was numerically solved in COMSOL Multiphysics. The results from the PBPK model after incorporating the brain permeability showed a good agreement (regression coefficient R2 = 0.825) with the in vivo results, verifying the capability of using the proposed PBPK model to predict the in vivo biodistribution of SPIO-Au-PEG NPs under the exposure to SMF. Furthermore, the in vivo results revealed that the brain bioavailability under the exposure to SMF (4.01%) is slightly better than the control group (3.68%). In addition, the modification of SPIO-Au-PEG NPs with insulin (SPIO-Au-PEG-insulin) showed an improvement of the brain bioavailability by 24.47 % in comparison to the non-insulin group. With the SMF stimulation, the brain bioavailability of SPIO-Au-PEG-insulin was further improved by 3.91 % compared to the group without SMF.
Disruption of synaptic transmission in the Bed Nucleus of the Stria Terminalis reduces seizure-induced death in DBA/1 mice and alters brainstem E/I balance
Authors: Xia Maya , Owen Benjamin , Chiang Jeremy , Levitt Alyssa , Yan Wen Wei , Nobis William P. 
Published: December 2021

ABSTRACTSudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Accumulating evidence from recent human studies and animal models suggests that seizure-related respiratory arrest may be important for initiating cardiorespiratory arrest and death. Prior evidence suggests that apnea onset can coincide with seizure spread to the amygdala and that stimulation of the amygdala can reliably induce apneas in epilepsy patients, potentially implicating amygdalar regions in seizure-related respiratory arrest and subsequent postictal hypoventilation and cardiorespiratory death. This study aimed to determine if an extended amygdalar structure, the dorsal bed nucleus of the stria terminalis (dBNST), is involved in seizure-induced respiratory arrest (S-IRA) and death using DBA/1 mice, a mouse strain which has audiogenic seizures and a high incidence of postictal respiratory arrest and death. The presence of S-IRA significantly increased c-Fos expression in the dBNST of DBA/1 mice. Furthermore, disruption of synaptic output from the dBNST via viral-induced tetanus neurotoxin significantly improved survival following S-IRA in DBA/1 mice without affecting baseline breathing or hypercapnic and hypoxic ventilatory response. This disruption in the dBNST resulted in changes to the balance of excitatory/inhibitory synaptic events in the downstream brainstem regions of the lateral parabrachial nucleus (PBN) and the periaqueductal gray (PAG). These findings suggest that the dBNST is a potential subcortical forebrain site necessary for the mediation of seizure-induced respiratory arrest, potentially through its outputs to brainstem respiratory regions.SUMMARY STATEMENTThis study used a viral expression technique to disrupt synaptic output in the bed nucleus of the stria terminalis (BNST) of DBA/1 audiogenic seizure mice. Inactivating the BNST significantly improved survival following seizures and altered brainstem excitation/inhibition balance.
Protein homeostasis is maintained by proteasomes containing PSMB9 induced by EEF1A2 upon mitochondrial stress
Authors: Kim Minji , Samluk Lukasz , Stępkowski Tomasz Maciej , Suppanz Ida , Serwa Remigiusz Adam , Kodroń Agata , Warscheid Bettina , Chacinska Agnieszka 
Published: December 2021

ABSTRACTPerturbed proteostasis and mitochondrial dysfunction are often associated with age-related diseases such as Alzheimer’s and Parkinson’s diseases. However, the link between them remains incompletely understood. Mitochondrial dysfunction causes proteostasis imbalance, and cells respond to restore proteostasis by increasing proteasome activity and molecular chaperons in yeast and C. elegans. Here, we demonstrate the presence of similar responses in humans. Mitochondrial dysfunction upregulates a small heat shock protein HSPB1 and an immunoproteasome subunit PSMB9 leading to an increase in proteasome activity. HSPB1 and PSMB9 are required to prevent protein aggregation upon mitochondrial dysfunction. Moreover, PSMB9 expression is dependent on a translation elongation factor EEF1A2, and PSMB9-containing proteasomes are located near mitochondria, enabling fast local degradation of aberrant proteins. Our findings put a step forward in understanding the stress response triggered by mitochondrial dysfunction, and may be useful for therapeutic strategies to prevent or delay the onset of age-related diseases and attenuate their progression.
Regulation of the PKD2 Channel Function by TACAN
Authors: Liu Xiong , Zhang Rui , Fatehi Mohammad , Wang Yifang , Long Wentong , Tian Rui , Deng Xiaoling , Weng Ziyi , Xu Qinyi , Light Peter E , Tang Jingfeng , Chen Xing-Zhen 
Published: December 2021

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in membrane receptor PKD1 or cation channel PKD2. TACAN (also named TMEM120A), recently reported as an ion channel in neuron cells for mechano and pain sensing, is also distributed in diverse non-neuronal tissues such as kidney, heart and intestine, suggesting its involvement in other functions. In this study, we found that TACAN is in complex with PKD2 in native renal cell lines. Using the two-electrode voltage clamp in Xenopus oocytes we found that TACAN inhibited the channel activity of PKD2 gain-of-function mutant F604P. The first and last transmembrane domains of TACAN were found to interact with the PKD2 C-and N-terminal portions, respectively. We showed that the TACAN N-terminus acted as a blocking peptide and that TACAN inhibits the PKD2 function through the PKD2/TACAN binding. By patch clamping in mammalian cells, we found that TACAN inhibits both the single channel conductance and open probability of PKD2 and mutant F604P. PKD2 co-expressed with TACAN, but not PKD2 alone, exhibited pressure sensitivity. Furthermore, we also found that TACAN aggravates PKD2-dependent tail curvature and pronephric cysts in larval zebrafish, in support of the in vitro inhibitory effects of TACAN. In summary, this study revealed that TACAN acts as a PKD2 inhibitor and mediates mechano sensitivity of the PKD2/TACAN channel complex.
XAB2 Dynamics during DNA Damage-Dependent Transcription Inhibition
Authors: Donnio Lise-Marie , Cerutti Elena , Magnani Charlène , Neuillet Damien , Mari Pierre-Olivier , Giglia-Mari Giuseppina 
Published: December 2021

ABSTRACTXeroderma Pigmentosum group A (XPA)-binding protein 2 (XAB2) is a multi-functional protein that plays a critical role in distinct cellular processes including transcription, splicing, DNA repair and mRNA export. In this study, we detailed XAB2 involvement during Nucleotide Excision Repair (NER), a repair pathway that guarantees genome integrity against UV light-induced DNA damage and that specifically removes transcription-blocking damage in a dedicated process known as Transcription-Coupled repair (TC-NER). Here, we demonstrated that XAB2 is involved specifically and exclusively in TC-NER reaction and solely for RNA Polymerase 2 transcribed genes. Surprisingly, contrary to all the other NER proteins studied so far, XAB2 does not accumulate on the local UV-C damage but on the contrary is remobilized after damage induction. This fast change in mobility is restored when DNA repair reactions are completed. By scrutinizing from which cellular complex/partner/structure XAB2 is released, we have identified that XAB2 is detached after DNA damage induction from the DNA:RNA hybrids, commonly known as R-loops, and from the CSA and XPG protein and this release is thought to contribute to the DNA damage recognition step during TC-NER. Importantly, we have disclosed a role for XAB2 in retaining RNAP2 on its substrate.
Hypersensitivity to uncertainty is key feature of subjective cognitive impairment
Authors: Attaallah Bahaaeddin , Petitet Pierre , Slavkova Elista , Turner Vicky , Saleh Youssuf , Manohar Sanjay G. , Husain Masud 
Published: December 2021

AbstractWith an increasingly ageing global population, more people are presenting with concerns about their cognitive function, but not all have an underlying neurodegenerative diagnosis. Subjective cognitive impairment (SCI) is a common condition describing self-reported deficits in cognition without objective evidence of cognitive impairment. Many individuals with SCI suffer from depression and anxiety, which have been hypothesised to account for their cognitive complaints. Despite this association between SCI and affective features, the cognitive and brain mechanisms underlying SCI are poorly understood. Here, we show that people with SCI are hypersensitive to uncertainty and that this might be a key mechanism accounting for their affective burden. Twenty-seven individuals with SCI performed an information sampling task, where they could actively gather information prior to decisions. Across different conditions, SCI participants sampled faster and obtained more information than matched controls to resolve uncertainty. Remarkably, despite their ‘urgent’ sampling behaviour, SCI participants were able to maintain their efficiency. Hypersensitivity to uncertainty indexed by this sampling behaviour correlated with the severity of affective burden including depression and anxiety. Analysis of MRI resting functional connectivity revealed that both uncertainty hypersensitivity and affective burden were associated with stronger insular-hippocampal connectivity. These results suggest that altered uncertainty processing is a key mechanism underlying the psycho-cognitive manifestations in SCI and implicate a specific brain network target for future treatment.
Neurons burdened by DNA double strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration
Authors: Welch Gwyneth , Boix Carles , Schmauch Eloi , Davila-Velderrain Jose , Victor Matheus B. , Dileep Vishnu , Bozzelli Lorenzo , Su Qiao , Cheng Jemmie , Lee Audrey , Leary Noelle , Pfenning Andreas , Kellis Manolis , Tsai Li-Huei 
Published: December 2021

AbstractDNA double strand breaks (DSBs) are linked to aging, neurodegeneration, and senescence1,2. However, the role played by neurons burdened with DSBs in disease-associated neuroinflammation is not well understood. Here, we isolate neurons harboring DSBs from the CK-p25 mouse model of neurodegeneration through fluorescence-activated nuclei sorting (FANS), and characterize their transcriptomes using single-nucleus, bulk, and spatial sequencing techniques. We find that neurons harboring DSBs enter a late-stage DNA damage response marked by the activation of senescent and antiviral-like immune pathways. We identify the NFkB transcription factor as a master regulator of immune gene expression in DSB-bearing neurons, and find that the expression of cytokines like Cxcl10 and Ccl2 develop in DSB-bearing neurons before glial cell types. Alzheimer’s Disease pathology is significantly associated with immune activation in excitatory neurons, and direct purification of DSB-bearing neurons from Alzheimer’s Disease brain tissue further validates immune gene upregulation. Spatial transcriptomics reveal that regions of brain tissue dense with DSB-bearing neurons also harbor signatures of inflammatory microglia, which is ameliorated by NFkB knock down in neurons. Inhibition of NFkB or depletion of Ccl2 and Cxcl10 in DSB-bearing neurons also reduces microglial activation in organotypic brain slice culture. In conclusion, we find that in the context of age-associated neurodegenerative disease, DSBs activate immune pathways in neurons, which in turn adopt a senescence associated secretory phenotype to elicit microglia activation. These findings highlight a novel role for neurons in the mechanism of age-associated neuroinflammation.SummaryIt is unclear how age-associated DNA double strand break (DSB) accumulation in neurons influences the progression of cellular senescence and neurodegenerative disease. Here, we leverage mouse models of neurodegeneration, single-nucleus, bulk, and spatial transcriptomics from Alzheimer’s disease patients, mouse models, and primary neuron cultures to dissect the immune signaling pathways initiated by DSB-bearing neurons that trigger neuroinflammation.
Pattern and component responses of primate MT neurons recorded with multi-contact electrodes, stimulated with 1D and 2D noise patterns
Authors: Quaia Christian , Kang Incheol , Cumming Bruce G 
Published: December 2021

Direction selective neurons in primary visual cortex (area V1) are affected by the aperture problem, i.e., they are only sensitive to motion orthogonal to their preferred orientation. A solution to this problem first emerges in the middle temporal (MT) area, where a subset of neurons (called pattern cells) combine motion information across multiple orientations and directions, becoming sensitive to pattern motion direction. These cells are expected to play a prominent role in subsequent neural processing, but they are intermixed with cells that behave like V1 cells (component cells), and others that do not clearly fall in either group. The picture is further complicated by the finding that cells that behave like pattern cells with one type of pattern, might behave like component cells for another.We recorded from macaque MT neurons using multi-contact electrodes while presenting both type I and unikinetic plaids, in which the components were 1D noise patterns. We found that the indices that have been used in the past to classify neurons as pattern or component cells work poorly when the properties of the stimulus are not optimized for the cell being recorded, as is always the case with multi-contact arrays. We thus propose alternative measures, which considerably ameliorate the problem, and allow us to gain insights in the signals carried by individual MT neurons.We conclude that arranging cells along a component-to-pattern continuum is an oversimplification, and that the signals carried by individual cells only make sense when embodied in larger populations.
Age-related susceptibility to grey matter demyelination and neurodegeneration is associated with meningeal neutrophil accumulation in an animal model of Multiple Sclerosis
Authors: Zuo Michelle , Fettig Naomi , Bernier Louis-Philippe , Pössnecker Elisabeth , Spring Shoshana , Pu Annie , Ma Xianjie I. , Lee Dennis S. W. , Ward Lesley , Sharma Anshu , Kuhle Jens , Sled John G. , Pröbstel Anne-Katrin , MacVicar Brian , Osborne Lisa , Gommerman Jennifer L. , Ramaglia Valeria 
Published: December 2021

AbstractPeople living with multiple sclerosis (MS) experience episodic central nervous system (CNS) white matter lesions instigated by autoreactive T cells. With age, MS patients show evidence of grey matter demyelination and experience devastating non-remitting symptomology. What drives progression is unclear and has been hampered by the lack of suitable animal models. Here we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induces a non-remitting clinical phenotype that is associated with persistent leptomeningeal inflammation and cortical pathology in old, but not young SJL/J mice. While the quantity and quality of T cells did not differ in the brains of old vs young EAE mice, an increase in neutrophils and a decrease in B cells was observed in the brains of old mice. Neutrophils were also found in the leptomeninges of a subset of progressive MS patient brains that showed evidence of leptomeningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and grey matter pathology are dictated by age and associated with other immune cells such as neutrophils.
Sensory axons induce epithelial lipid microdomain remodeling and determine the distribution of junctions in the epidermis
Authors: Rosa Jeffrey B. , Nassman Khaled Y. , Sagasti Alvaro 
Published: December 2021

AbstractEpithelial cell properties are determined by the polarized distribution of membrane lipids, the cytoskeleton, and adhesive junctions. Epithelia are often profusely innervated, but little work has addressed how contact with neurites affects the polarized organization of epithelial components. In previous work, we found that basal keratinocytes in the larval zebrafish epidermis wrap around axons to enclose them in ensheathment channels sealed by autotypic cell junctions. In this study, we used live imaging to characterize how sensory axons remodel cell membranes, the actin cytoskeleton, and adhesive junctions in basal keratinocytes. At the apical surface of basal keratinocytes, axons promoted the formation of lipid microdomains quantitatively enriched in reporters for PI(4,5)P2 and liquid-ordered (Lo) membranes. Lipid microdomains supported the formation of cadherin-enriched F-actin protrusions, which wrapped around axons, likely initiating the formation of ensheathment channels. Lo reporters, but not reporters of liquid-disordered (Ld) membranes, became progressively enriched at axon-associated membrane domains as autotypic junctions matured at ensheathment channels. In the absence of axons, cadherin-enriched lipid microdomains still formed on basal cell membranes, but were not organized into the contiguous domains normally associated with axons. Instead, these isolated domains formed ectopic heterotypic junctions with overlying periderm cells, a distinct epithelial cell type in the epidermis. Thus, axons inhibit the formation of epithelial heterotypic junctions by recruiting cadherin-rich lipid microdomains to form autotypic junctions at ensheathment channels. These findings demonstrate that sensory nerve endings dramatically remodel polarized epithelial components and regulate the adhesive properties of the epidermis.
Profiling the Landscape of Drug Resistance Mutations in Neosubstrates to Molecular Glue Degraders
Authors: Gosavi Pallavi M. , Ngan Kevin C. , Yeo Megan , Su Cindy , Li Jiaming , Lue Nicholas Z. , Hoenig Samuel M. , Liau Brian B. 
Published: December 2021

AbstractTargeted protein degradation (TPD) holds immense promise for drug discovery but mechanisms of acquired resistance to degraders remain to be fully identified. Here we used CRISPR-suppressor scanning to identify mechanistic classes of drug resistance mutations to molecular glue degraders in GSPT1 and RBM39, neosubstrates targeted by E3 ligase substrate receptors cereblon and DCAF15, respectively. While many mutations directly alter the ternary complex heterodimerization surface, distal resistance sites were also identified. Several distal mutations in RBM39 led to modest decreases in degradation yet can enable cell survival, underscoring how small differences in degradation can lead to resistance. Integrative analysis of resistance sites across GSPT1 and RBM39 revealed varying levels of sequence conservation and mutational constraint that control the emergence of different resistance mechanisms, highlighting that many regions co-opted by TPD are inessential. Altogether, our study identifies common resistance mechanisms for molecular glue degraders and outlines a general approach to survey neosubstrate requirements necessary for effective degradation.
Pharmacological blockade of muscle afferents and perception of effort: a systematic review with meta-analysis
Authors: Bergevin Maxime , Steele James , Payen de la Garanderie Marie , Feral-Basin Camille , Marcora Samuele M. , Rainville Pierre , Caron Jeffrey G. , Pageaux Benjamin 
Published: December 2021

AbstractBackgroundThe perception of effort (PE) provides information on task difficulty and influences physical exercise regulation and human behavior. This perception differs from other-exercise related perceptions such as pain. There is no consensus on the role of group III-IV muscle afferents as a signal processed by the brain to generate PE.ObjectiveThe aim of this meta-analysis was to investigate the effect of pharmacologically blocking muscle afferents on the PE.MethodsSix databases were searched to identify studies measuring the ratings of perceived effort (RPE) during physical exercise, with and without pharmacological blockade of muscle afferents. Articles were coded based on the operational measurement used to distinguish studies in which PE was assessed specifically (effort dissociated) or as a composite experience including other exercise-related perceptions (effort not dissociated). Articles that did not provide enough information for coding were assigned to theuncleargroup.ResultsTheeffort dissociatedgroup (n=6) demonstrated a slight RPE increase with reduced muscle afferents feedback (standard mean change raw (SMCR), 0.39; 95%CI, 0.13 to 0.64). The groupeffort not dissociated(n=2) did not reveal conclusive results (SMCR, −0.29; 95%CI, −2.39 to 1.8). The groupunclear(n=8) revealed a slight RPE decrease with reduced muscle afferents feedback (SMCR, −0.27; 95%CI, −0.50 to −0.04).ConclusionsThe heterogeneity in results between groups reveals that the inclusion of perceptions other than effort in its rating influences the RPE scores reported by the participants. The absence of decreased RPE in theeffort dissociatedgroup suggests that muscle afferents feedback is not a sensory signal of PE.Key pointsTo date, there is no consensus on the neurophysiological signal processed by the brain to generate the perception of effort.Following a systematic search in six databases, this meta-analysis suggests that reducing afferent feedback from the working muscles via epidural anesthesia does not reduce perception of effort.This systematic review suggests that afferent feedback from the working muscles is not the neurophysiological signal processed by the brain to generate the perception of effort.