Biology subjects

Niu, M.

Publications and source records attributed to Niu, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Late-Life Alcohol Exposure Does Not Exacerbate Age-Dependent Reductions in Mouse Spatial Memory and Brain TFEB Activity

Alcohol consumption is believed to affect Alzheimers disease (AD) risk, but the contributing mechanisms are not well understood. A potential mediator of the proposed alcohol-AD connection is autophagy, a degradation pathway that maintains organelle and protein homeostasis. Autophagy is in turn regulated through the activity of Transcription factor EB (TFEB), which promotes lysosome and autophagy-related gene expression. To explore the effect of alcohol on brain TFEB and autophagy, we exposed young (3-month old) and aged (23-month old) mice to two alcohol-feeding paradigms and assessed biochemical, transcriptome, histology, and behavioral endpoints. In young mice, alcohol decreased hippocampal nuclear TFEB staining but increased SQSTM1/p62, LC3-II, ubiquitinated proteins, and phosphorylated Tau. Hippocampal TFEB activity was lower in aged mice than it was in young mice, and Gao-binge alcohol feeding did not worsen the age-related reduction in TFEB activity. To better assess the impact of chronic alcohol exposure, we fed young and aged mice alcohol for four weeks before completing Morris Water and Barnes Maze spatial memory testing. The aged mice showed worse spatial memory on both tests. While alcohol feeding slightly impaired spatial memory in the young mice, it had little effect or even slightly improved spatial memory in the aged mice. These findings suggest that aging is a far more important driver of spatial memory impairment and reduced autophagy flux than alcohol consumption.

animal behavior and cognition↗

bioRxiv2023

Characterization of Cancer Evolution Landscape Based on Accurate Detection of Somatic Mutations in Single Tumor Cells

Accurate detection of somatic mutations in single tumor cells is greatly desired as it allows us to quantify the single-cell mutation burden and construct the mutation-based phylogenetic tree. Here we developed scNanoSeq chemistry and profiled 842 single cells from 21 human breast cancer samples. The majority of the mutation-based phylogenetic trees comprise a characteristic stem evolution followed by the clonal sweep. We observed the subtype-dependent lengths in the stem evolution. To explain this phenomenon, we propose that the differences are related to different reprogramming required for different subtypes of breast cancer. Furthermore, we reason that the time that the tumor-initiating cell took to acquire the critical clonal-sweep-initiating mutation by random chance set the time limit for the reprogramming process. We refer to this model as a reprogramming and critical mutation co-timing (RCMC) subtype model. Next, in the sweeping clone, we observed that tumor cells undergo a branched evolution with rapidly decreasing selection. In the most recent clades, effectively neutral evolution has been reached, resulting in a substantially large number of mutational heterogeneities. Integrative analysis with 522-713X ultra-deep bulk whole genome sequencing (WGS) further validated this evolution mode. Mutation-based phylogenetic trees also allow us to identify the early branched cells in a few samples, whose phylogenetic trees support the gradual evolution of copy number variations (CNVs). Overall, the development of scNanoSeq allows us to unveil novel insights into breast cancer evolution.

genomics↗

bioRxiv2023

MEBRAINS 1.0: a new population-based macaque atlas

Due to their fundamental relevance, the number of anatomical macaque brain templates is constantly growing. Novel templates aim to alleviate limitations of previously published atlases and offer the foundation to integrate multiscale multimodal data. Typical limitations of existing templates include their reliance on one subject, their unimodality (usually only T1 or histological images), or lack of anatomical details. The MEBRAINS template overcomes these limitations by using a combination of T1 and T2 images, from the same 10 animals (Macaca mulatta), which are averaged by the multi-brain toolbox for diffeomorphic registration and segmentation. The resulting volumetric T1 and T2 templates are supplemented with high quality white and gray matter surfaces built with FreeSurfer. Human-curated segmentations of pial surface, white/gray matter interface and major subcortical nuclei were used to analyse the relative quality of the MEBRAINS template. Recently published 3D maps of the macaque inferior parietal lobe and (pre)motor cortex were warped to the MEBRAINS surface template, thus populating it with a parcellation scheme based on cyto- and receptor architectonic analyses. Finally, 9 CT scans of the same monkeys were registered to the T1 modality and co-registered to the template. Through its main features (multi-subject, multi-modal, volume-and-surface, traditional and deep learning-based segmentations), MEBRAINS aims to improve integration of multi-modal multi-scale macaque data and is quantitatively equal or better compared to currently widely used macaque templates. The template is integrated in the EBRAINS and Scalable Brain Atlas web-based infrastructures, each of which comes with its own suite of spatial registration tools.

neuroscience↗

bioRxiv2023

Step-wise mechanical unfolding and dissociation of the GAIN domains of ADGRG1/GPR56, ADGRL1/Latrophilin-1 and ADGRB3/BAI3: insights into the mechanical activation hypothesis of adhesion G protein-coupled receptors

Adhesion G protein-coupled receptors (aGPCRs) are a large family within the superfamily of G protein-coupled receptors involved in various physiological processes. One unique feature of aGPCRs is their long N-terminal extracellular regions (ECRs), which contain adhesive domains and a GPCR autoproteolysis-inducing (GAIN) domain. This GAIN domain promotes autoproteolytic cleavage of aGPCRs into N- and C-terminal fragments (NTF, CTF, respectively) after receptor biosynthesis. aGPCR signaling involves an interplay between the NTF and CTF that can be me-chanically activated or modulated. However, how force affects the conformation/structure of the GAIN domain as a central structural element in aGPCR activation remains largely unknown. In this study, we investigated the mechanical stability of the GAIN domains of three aGPCRs from subfamilies B, G and L at a loading rate of 1 pN/s. Our findings demonstrate that the GAIN domains can be destabilized by forces from a few to 20 piconewtons (pN). Specifically, for the autocleaved aGPCRs, ADGRG1/GPR56 and ADGRL1/Latrophilin-1, forces over this range can cause detachment of the GAIN domain from the membrane-proximal Stachel element, which serves as an endogenous tethered agonist to aGPCRs, typically preceded with GAIN domain unfolding. For the non-cleavable aGPCR ADGRB3/BAI3, the GAIN domain undergoes complex mechanical unfolding over a similar force range. We also demonstrate that detachment of the GAIN domain can take place during cell migration, provided that the linkage between aGPCR and extracellular matrix is sufficiently stable. These results suggest that both structural stability of the GAIN domain and NTF/CTF dissociation are sensitive to physiological ranges of tensile forces, providing insights into the mechanical activation hypothesis of aGPCRs.

biophysics↗

bioRxiv2023

Influence of HIV-1 genomic RNA on the formation of Gagbiomolecular condensates

Biomolecular condensates (BMCs) play an important role in the replication of a growing number of viruses, but many important mechanistic details remain to be elucidated. Previously, we demonstrated that pan-retroviral nucleocapsid (NC) and the HIV-1 pr55Gag (Gag) proteins phase separate into condensates, and that HIV-1 protease (PR)-mediated maturation of Gag and Gag-Pol precursor proteins yield self-assembling BMCs having HIV-1 core architecture. Using biochemical and imaging techniques, we aimed to further characterize the phase separation of HIV-1 Gag by determining which of its intrinsically disordered regions (IDRs) influence the formation of BMCs and how the HIV-1 viral genomic RNA (gRNA) could influence BMC abundance and size. We found that mutations in the Gag matrix (MA) domain or the NC zinc finger motifs altered condensate number and size in a salt-dependent manner. Gag BMCs were also bimodally influenced by the gRNA, with a condensate-promoting regime at lower protein concentrations and a gel dissolution at higher protein concentrations. Interestingly, incubation of Gag with CD4+ T cell nuclear lysates led to the formation of larger BMCs as compared to much smaller ones observed in the presence of cytoplasmic lysates. These findings suggests that the composition and properties of Gag-containing BMCs may be altered by differential association of host factors in nuclear and cytosolic compartments during virus assembly. This study significantly advances our understanding of HIV-1 Gag BMC formation and provides a foundation for future therapeutic targeting of virion assembly.

microbiology↗

bioRxiv2022

Taxonomic and carbon metabolic diversification of Bathyarchaeia during its co-evolution history with the early Earth surface environment

Bathyarchaeia, as one of the most abundant microorganisms on Earth, play vital roles in the global carbon cycle. However, our understanding of their origin, evolution and ecological functions remains poorly constrained. Based on the phylogeny of the present largest dataset of Bathyarchaeia metagenome assembled genome (MAG), we reclassified Bathyarchaeia into eight order-level units and corresponded to the former subgroup system. Highly diversified and versatile carbon metabolisms were discovered among different orders, particularly atypical C1 metabolic pathways, indicating that Bathyarchaeia represent overlooked important methylotrophs. Molecular dating results indicate that Bathyarchaeia diverged at [~]3.3 Ga, followed by three major diversifications at [~]3.0 Ga, [~]2.5 Ga and [~]1.8-1.7 Ga, likely driven by continental emergence, growth and intensive submarine volcanism, respectively. The lignin-degrading Bathyarchaeia clade emerged at [~]300 Ma and perhaps contributed to the sharply decreased carbon sequestration rate during the Late Carboniferous period. The evolutionary pathway of Bathyarchaeia potentially have been shaped by geological forces, which in turn impacted the Earths surface environment. TeaserThe origin and divergence of Bathyarchaeia linked to the early Earth tectonics and surface environment changes

microbiology↗

bioRxiv2022

Morphine Suppresses Peripheral Responses and Transforms Brain Myeloid Gene Expression to Favor Neuropathogenesis in SIV Infection

The twin pandemics of opioid abuse and HIV infection can have devastating effects on physiological systems, including on the brain. Our previous work found that morphine increased the viral reservoir in the brains of treated SIV-infected macaques. In this study, we investigated the interaction of morphine and SIV to identify novel host-specific targets using a multimodal approach. We probed systemic parameters and performed single-cell examination of the targets for infection in the brain, microglia and macrophages. Morphine treatment created an immunosuppressive environment, blunting initial responses to infection, which persisted during antiretroviral treatment. Antiretroviral drug concentrations and penetration into the cerebrospinal fluid and brain were unchanged by morphine treatment. Interestingly, the transcriptional signature of both microglia and brain macrophages was transformed to one of a neurodegenerative phenotype. Notably, the expression of osteopontin, a pleiotropic cytokine, was significantly elevated in microglia. This was especially notable in the white matter, which is also dually affected by HIV and opioids. Increased osteopontin expression was linked to numerous HIV neuropathogenic mechanisms, including those that can maintain a viral reservoir. The opioid morphine is detrimental to SIV/HIV infection, especially in the brain.

neuroscience↗

bioRxiv2022

Cytoarchitectonic, receptor distribution and functional connectivity analyses of the macaque frontal lobe

Based on quantitative cyto- and receptor architectonic analyses, we identified 35 prefrontal areas and introduced a novel subdivision of Walkers areas 10, 9, 8B and 46. Statistical analysis of receptor densities revealed regional differences in lateral and ventrolateral prefrontal cortex. Since structural and functional organization of subdivisions encompassing areas 46 and 12 demonstrated significant differences in the interareal levels of 2 receptors. Furthermore, multivariate analysis included receptor fingerprints of previously identified 16 motor areas in the same macaque brains, and revealed five clusters encompassing frontal lobe areas. Based on the functional connectivity analysis, clustered areas showed similar connectivity distribution pattern. In particular, rostrally located areas (in clusters 1-2) were characterized by bigger fingerprints, i.e., higher receptor densities, and stronger regional interconnections. Whereas, more caudal areas (in clusters 3-5) had smaller fingerprints, but showed a widespread connectivity pattern with distant cortical regions. Taken together, present study provides a comprehensive insight into the molecular structure underlying the functional organization of the cortex and, thus, reconcile discrepancies between the structural and functional hierarchical organization of the primate frontal lobe. Finally, our data are publicly available via the EBRAINS and BALSA repositories for the entire scientific community.

neuroscience↗

bioRxiv2022

A connectome-based model of conscious access in monkey cortex

A growing body of evidence suggests that conscious perception of a sensory stimulus coincides with all-or-none activity across multiple cortical areas, a phenomenon called ignition. In contrast, the same stimulus, when undetected, induces only transient activity. In this work, we report a large-scale model of the macaque cortex based on recently quantified structural mesoscopic connectome data. We use this model to simulate a detection task, and demonstrate how a dynamical bifurcation mechanism produces ignition-like events in the model network. The model predicts that feedforward excitatory transmission is primarily mediated by the fast AMPA receptors to ensure rapid signal propagation from sensory to associative areas. In contrast, a greater proportion of the inter-areal feedback projections and local recurrent excitation depend on the slow NMDA receptors, to ensure ignition of distributed frontoparietal activity. Our model predicts, counterintuitively, that fast-responding sensory areas contain a higher ratio of NMDA to AMPA receptors compared to association cortical areas that show slow, sustained activity. We validate this prediction using cortex-wide in-vitro receptor autoradiography data. Finally, we show how this model can account for various behavioral and physiological effects linked to consciousness. Together, these findings clarify the neurophysiological mechanisms of conscious access in the primate cortex and support the concept that gradients of receptor densities along the cortical hierarchy contribute to distributed cognitive functions.

neuroscience↗

bioRxiv2021

Cyclooxygenase production of PGE2 promotes phagocyte control of A. fumigatus hyphal growth in larval zebrafish

Invasive aspergillosis is a common opportunistic infection, causing >50% mortality in infected immunocompromised patients. The specific molecular mechanisms of the innate immune system that prevent pathogenesis of invasive aspergillosis in immunocompetent individuals are not fully understood. Here, we used a zebrafish larva-Aspergillus infection model to identify cyclooxygenase (COX) enzyme signaling as one mechanism that promotes host survival. Larvae exposed to the pan-COX inhibitor indomethacin succumb to infection at a significantly higher rate than control larvae. COX signaling is both macrophage- and neutrophil-mediated. However, indomethacin treatment has no effect on phagocyte recruitment. Instead, COX signaling promotes phagocyte-mediated inhibition of germination and invasive hyphal growth. Protective COX-mediated signaling requires the receptor EP2 and exogenous prostaglandin E2 (PGE2) rescues indomethacin-induced decreased immune control of fungal growth. Collectively, we find that COX signaling activates the PGE2-EP2 pathway to increase control A. fumigatus hyphal growth by phagocytes in zebrafish larvae. Author SummaryInvasive aspergillosis causes mortality in >50% of infected patients. It is caused by a free-living fungus Aspergillus fumigatus which releases thousands of airborne spores. While healthy individuals clear inhaled spores efficiently, in immunocompromised individuals these spores grow into filamentous hyphae and destroy lungs and other tissues causing invasive aspergillosis. The immune mechanisms that control this fungal growth in healthy people are still largely unknown. Here, we used a larval zebrafish model of A. fumigatus infection to determine that cyclooxygenase enzymes, which are the target of non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen, are important to control the fungus. Innate immune cells use cyclooxygenase signaling to prevent hyphal growth and tissue destruction. Our study provides new insights into the mechanisms that immune cells deploy to stop invasive growth of A. fumigatus and inform development of future strategies to combat invasive aspergillosis.

immunology↗

bioRxiv2021

SMAP: A pipeline for sample matching in proteogenomics

Integration of genomics and proteomics (proteogenomics) offers unprecedented promise for in-depth understanding of human diseases. However, sample mix-up is a pervasive, recurring problem, due to complex sample processing in proteogenomics. Here we present a pipeline for Sample Matching in Proteogenomics (SMAP) for verifying sample identity to ensure data integrity. SMAP infers sample-dependent protein-coding variants from quantitative mass spectrometry (MS), and aligns the MS-based proteomic samples with genomic samples by two discriminant scores. Theoretical analysis with simulation data indicates that SMAP is capable of uniquely match proteomic and genomic samples, when [≥]20% genotypes of individual samples are available. When SMAP was applied to a large-scale proteomics dataset from 288 biological samples generated by the PsychENCODE BrainGVEX project, we identified and corrected 18.8% (54/288) mismatched samples. The correction was further confirmed by ribosome profiling and assay for transposase-accessible chromatin sequencing data from the same set of samples. Thus our results demonstrate that SMAP is an effective tool for sample verification in a large-scale MS-based proteogenomics study. The source code, manual, and sample data of the SMAP are publicly available at https://github.com/UND-Wanglab/SMAP, and a web-based SMAP can be accessed at https://smap.shinyapps.io/smap/.

bioinformatics↗

bioRxiv2021

Prevalent uses of exons as regulatory sequences are possible and inevitable

BackgroundIt has long been known that exons can be used as cis-regulatory sequences such as enhancers. However, the prevalence of such dual-use of exons and how they evolve remain elusive. Our recently predicted highly accurate, large sets of cis-regulatory module candidates (CRMCs) and non-CRMCs in the human genome positioned us to address these questions. ResultsWe found that exonic transcription factor binding sites (TFBSs) occupied at least a third of the total exon lengths, and 96.7% of genes had exonic TFBSs. Both A/T and C/G in exonic TFBSs are more likely under evolutionary constraints than those in non-CRMC exons. Interestingly, exonic TFBSs in codons tend to encode loops rather than more critical helices and strands in protein structures, while exonic TFBSs in untranslated regions (UTRs) tend to avoid positions where known UTR-related functions are located. Moreover, active exonic TFBSs tend to be in close physical proximity to distal promoters whose immediately downstream genes have elevated transcription levels, suggesting that they might be involved in transcriptional regulation of target genes. It is highly possible that less critical positions in an exon that is physically close to a promoter can evolve into a TFBS when no non-exonic sequences are physically available to the promoter. ConclusionsExonic TFBSs might be more prevalent than originally thought and are likely in dual-use. Possible detrimental effects caused by such dual-use can be reduced by using less critical exonic positions. We proposed a parsimonious model to explain how a stretch of codons evolve into a TFBS.

evolutionary biology↗

bioRxiv2021

Gradients of receptor expression in the macaque cortex

Dynamics and functions of neural circuits depend on synaptic interactions mediated by receptors. Therefore, a comprehensive map of receptor organization is needed to understand how different functions may emerge across distinct cortical regions. Here we use in-vitro receptor autoradiography to measure the density of 14 neurotransmitter receptor types in 109 areas of macaque cortex. We integrate the receptor data with other anatomical, genetic and functional connectivity data into a common cortical space. We uncovered a principal gradient of increasing receptor expression per neuron aligned with cortical hierarchy from early sensory cortex to higher cognitive areas. A second gradient, primarily driven by 5-HT1A receptors, peaks in the anterior and subcallosal cingulate, suggesting that the macaque may be a promising animal model for major depressive disorder. The receptor gradients may enable rapid, reliable information processing in sensory cortical areas and slow, flexible integration of information in higher cognitive areas.

neuroscience↗

bioRxiv2021

Inhibition of HSP90 reversed STAT3 mediated muscle wasting induced by cancer cachexia

Cancer cachexia is one of the most common causes of death among cancer patients, no effective anti-cachectic treatment is currently available. In experimental cachectic models, aberrant activation of STAT3 in skeletal muscle has been found to contribute to muscle wasting. However, its clinical association, the factors regulating STAT3 activation, and the molecular mechanisms of STAT3-induced muscle atrophy in cancer cachexia remain incompletely understood. Here, we show that an enhanced interaction between STAT3 and HSP90, which causes the persistent STAT3 activation in the skeletal muscle of cancer cachexia patients, is the crucial event for the development of cachectic muscle wasting. Administration of HSP90 inhibitors alleviated the muscle wasting in C26 tumor-bearing cachetic mice model or C26 conditional medium induced C2C12 myotube atrophy. A mechanistic study indicated that in cachectic skeletal muscle, prolonged STAT3 activation triggered muscle wasting in a FOXO1-dependent manner, STAT3 activated FOXO1 by binding directly to its promoter. Our results provide key insights into the role of the HSP90/STAT3/FOXO1 axis in cachectic muscle wasting, which shows promising therapeutic potential as a target for the treatment of cancer cachexia.

pathology↗

bioRxiv2020

The bone microenvironment invigorates metastatic seeds for further dissemination

Metastasis has been considered as the terminal step of tumor progression. However, recent clinical studies suggest that many metastases are seeded from other metastases, rather than primary tumors. Thus, some metastases can further spread, but the corresponding pre-clinical models are lacking. By using several approaches including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. Importantly, dissemination from the bone microenvironment appears to be more aggressive compared to that from mammary tumors and lung metastases. We further uncovered that this metastasis-promoting effect is independent from genetic selection, as single cell-derived cancer cell populations (SCPs) exhibited enhanced metastasis capacity after being extracted from the bone microenvironment. Taken together, our work revealed a previously unappreciated effect of the bone microenvironment on metastasis evolution, and suggested a stable reprogramming process that engenders cancer cells more metastatic.

cancer biology↗

bioRxiv2020

Multimodal 3D atlas of the macaque monkey motor and premotor cortex

In the present study we reevaluated the parcellation scheme of the macaque frontal agranular cortex by implementing quantitative cytoarchitectonic and multireceptor analyses, with the purpose to integrate and reconcile the discrepancies between previously published maps of this region. We applied an observer-independent and statistically testable approach to determine the position of cytoarchitectonic borders. Analysis of the regional and laminar distribution patterns of 13 different transmitter receptors confirmed the position of cytoarchitectonically identified borders. Receptor densities were extracted from each area and visualized as its "receptor fingerprint". Hierarchical and principal components analyses were conducted to detect clusters of areas according to the degree of (dis)similarity of their fingerprints. Finally, functional connectivity pattern of each identified area was analyzed with areas of prefrontal, cingulate, somatosensory and lateral parietal cortex and the results were depicted as "connectivity fingerprints" and seed-to-vertex connectivity maps. We identified 16 cyto- and receptor architectonically distinct areas, including novel subdivisions of the primary motor area 4 (i.e. 4a, 4p, 4m) and of premotor areas F4 (i.e. F4s, F4d, F4v), F5 (i.e. F5s, F5d, F5v) and F7 (i.e. F7d, F7i, F7s). Multivariate analyses of receptor fingerprints revealed three clusters, which first segregated the subdivisions of area 4 with F4d and F4s from the remaining premotor areas, then separated ventrolateral from dorsolateral and medial premotor areas. The functional connectivity analysis revealed that medial and dorsolateral premotor and motor areas show stronger functional connectivity with areas involved in visual processing, whereas 4p and ventrolateral premotor areas presented a stronger functional connectivity with areas involved in somatomotor responses. For the first time, we provide a 3D atlas integrating cyto- and multi-receptor architectonic features of the macaque motor and premotor cortex. This atlas constitutes a valuable resource for the analysis of functional experiments carried out with non-human primates, for modeling approaches with realistic synaptic dynamics, as well as to provide insights into how brain functions have developed by changes in the underlying microstructure and encoding strategies during evolution. HighlightsO_LIMultimodal analysis of macaque motor and premotor cortex reveals novel parcellation C_LIO_LI3D atlas with cyto- and multireceptor architectonic features of 16 (pre)motor areas C_LIO_LIPrimary motor area 4 is cyto- and receptor architectonically heterogeneous C_LIO_LI(Pre)motor areas differ in their functional connectivity fingerprints C_LI

neuroscience↗

bioRxiv2020

High-Throughput Analysis of Lung Immune Cells in a Murine Model of Rheumatoid Arthritis-Associated Lung Disease

Rheumatoid arthritis (RA)-associated lung disease is a leading cause of mortality in RA, yet the mechanisms linking lung disease and RA remain unknown. Using an established murine model of RA-associated lung disease combining collagen-induced arthritis (CIA) with organic dust extract (ODE)-induced airway inflammation, differences among lung immune cell populations were analyzed by single cell RNA-sequencing. Additionally, four lung myeloid-derived immune cell populations including macrophages, monocytes/macrophages, monocytes, and neutrophils were isolated by fluorescence cell sorting and gene expression was determined by NanoString analysis. Unsupervised clustering revealed 14 discrete clusters among Sham, CIA, ODE, and CIA+ODE treatment groups: 3 neutrophils (inflammatory, resident/transitional, autoreactive/suppressor), 5 macrophages (airspace, differentiating/recruited, recruited, resident/interstitial, and proliferative airspace), 2 T-cells (differentiating and effector), and a single cluster each of inflammatory monocytes, dendritic cells, B-cells and natural killer cells. Inflammatory monocytes, autoreactive/suppressor neutrophils, and recruited/differentiating macrophages were predominant with arthritis induction (CIA and CIA+ODE). By specific lung cell isolation, several interferon-related and autoimmune genes were disproportionately expressed among CIA and CIA+ODE (e.g. Oasl1, Oas2, Ifit3, Gbp2, Ifi44, and Zbp1), corresponding to RA and RA-associated lung disease. Monocytic myeloid-derived suppressor cells were reduced, while complement genes (e.g. C1s1 and Cfb) were uniquely increased in CIA+ODE mice across cell populations. Recruited and inflammatory macrophages/monocytes and neutrophils expressing interferon-, autoimmune-, and complement-related genes might contribute towards pro-fibrotic inflammatory lung responses following airborne biohazard exposures in setting of autoimmune arthritis and could be predictive and/or targeted to reduce disease burden.

immunology↗

bioRxiv2020

A dopamine gradient controls access to distributed working memory in monkey cortex

Dopamine is critical for working memory. However, its effects throughout the large-scale primate cortex are poorly understood. Here we report that dopamine receptor density per neuron, measured by receptor autoradiography in the macaque monkey cortex, displays a macroscopic gradient along the cortical hierarchy. We developed a connectome- and biophysically-based model for distributed working memory that incorporates multiple neuron types and a dopamine gradient. The model captures an inverted U-shaped dependence of working memory on dopamine. The spatial distribution of mnemonic persistent activity matches that observed in over 90 experimental studies. We show that dopamine filters out irrelevant stimuli by enhancing inhibition of pyramidal cell dendrites. The level of cortical dopamine can also determine whether memory encoding is through persistent activity or an internal synaptic state. Taken together, our work represents a cross-level understanding that links molecules, cell types, recurrent circuit dynamics and a core cognitive function distributed across the cortex.

neuroscience↗