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Signal Transduction and Targeted Therapy Nov 2022SARS-CoV-2 Omicron variant infection generally gives rise to asymptomatic to moderate COVID-19 in vaccinated people. The immune cells can be reprogrammed or "imprinted"...
SARS-CoV-2 Omicron variant infection generally gives rise to asymptomatic to moderate COVID-19 in vaccinated people. The immune cells can be reprogrammed or "imprinted" by vaccination and infections to generate protective immunity against subsequent challenges. Considering the immune imprint in Omicron infection is unclear, here we delineate the innate immune landscape of human Omicron infection via single-cell RNA sequencing, surface proteome profiling, and plasma cytokine quantification. We found that monocyte responses predominated in immune imprints of Omicron convalescents, with IL-1β-associated and interferon (IFN)-responsive signatures with mild and moderate symptoms, respectively. Low-density neutrophils increased and exhibited IL-1β-associated and IFN-responsive signatures similarly. Mild convalescents had increased blood IL-1β, CCL4, IL-9 levels and PI3 neutrophils, indicating a bias to IL-1β responsiveness, while moderate convalescents had increased blood CXCL10 and IFN-responsive monocytes, suggesting durative IFN responses. Therefore, IL-1β- or IFN-responsiveness of myeloid cells may indicate the disease severity of Omicron infection and mediate post-COVID conditions.
Topics: Humans; COVID-19; SARS-CoV-2; Cytokines; Immunity, Innate
PubMed: 36379915
DOI: 10.1038/s41392-022-01237-y -
Cells Jun 2023Apathy is commonly defined as a loss of motivation leading to a reduction in goal-directed behaviors. This multidimensional syndrome, which includes cognitive, emotional... (Review)
Review
Apathy is commonly defined as a loss of motivation leading to a reduction in goal-directed behaviors. This multidimensional syndrome, which includes cognitive, emotional and behavioral components, is one of the most prevalent neuropsychiatric features of Parkinson's disease (PD). It has been established that the prevalence of apathy increases as PD progresses. However, the pathophysiology and anatomic substrate of this syndrome remain unclear. Apathy seems to be underpinned by impaired anatomical structures that link the prefrontal cortex with the limbic system. It can be encountered in the prodromal stage of the disease and in fluctuating PD patients receiving bilateral chronic subthalamic nucleus stimulation. In these stages, apathy may be considered as a disorder of motivation that embodies amotivational behavioral syndrome, is underpinned by combined dopaminergic and serotonergic denervation and is dopa-responsive. In contrast, in advanced PD patients, apathy may be considered as cognitive apathy that announces cognitive decline and PD dementia, is underpinned by diffuse neurotransmitter system dysfunction and Lewy pathology spreading and is no longer dopa-responsive. In this review, we discuss the clinical patterns of apathy and their treatment, the neurobiological basis of apathy, the potential role of the anatomical structures involved and the pathways in motivational and cognitive apathy.
Topics: Humans; Apathy; Parkinson Disease; Depression; Limbic System; Syndrome; Dihydroxyphenylalanine
PubMed: 37371068
DOI: 10.3390/cells12121599 -
Autophagy Apr 2021Proteome profiling and global protein-interaction approaches have significantly improved our knowledge of the protein interactomes of autophagy and other cellular...
Proteome profiling and global protein-interaction approaches have significantly improved our knowledge of the protein interactomes of autophagy and other cellular stress-response pathways. New discoveries regarding protein complexes, interaction partners, interaction domains, and biological roles of players that are part of these pathways are emerging. The fourth Vancouver Autophagy Symposium showcased research that expands our understanding of the protein interaction networks and molecular mechanisms underlying autophagy and other cellular stress responses in the context of distinct stressors. In the keynote presentation, Dr. Wade Harper described his team's recent discovery of a novel reticulophagy receptor for selective autophagic degradation of the endoplasmic reticulum, and discussed molecular mechanisms involved in ribophagy and non-autophagic ribosomal turnover. In other presentations, both omic and targeted approaches were used to reveal molecular players of other cellular stress responses including amyloid body and stress granule formation, anastasis, and extracellular vesicle biogenesis. Additional topics included the roles of autophagy in disease pathogenesis, autophagy regulatory mechanisms, and crosstalk between autophagy and cellular metabolism in anti-tumor immunity. The relationship between autophagy and other cell stress responses remains a relatively unexplored area in the field, with future investigations required to understand how the various processes are coordinated and connected in cells and tissues. A-bodies: amyloid bodies; ACM: amyloid-converting motif; AMFR/gp78: autocrine motility factor receptor; ATG: autophagy-related; ATG4B: autophagy related 4B cysteine peptidase; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CAR T: chimeric antigen receptor T; CASP3: caspase 3; CCPG1: cell cycle progression 1; CAR: chimeric antigen receptor; CML: chronic myeloid leukemia; CCOCs: clear cell ovarian cancers; CVB3: coxsackievirus B3; CRISPR-Cas9: clustered regularly interspaced short palindromic repeats-CRISPR associated protein 9; DDXs: DEAD-box helicases; EIF2S1/EIF-2alpha: eukaryotic translation initiation factor 2 subunit alpha; EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; EV: extracellular vesicle; FAO: fatty acid oxidation; GABARAP: GABA type A receptor-associated protein; ILK: integrin linked kinase; ISR: integrated stress response; MTOR: mechanistic target of rapamycin kinase; MPECs: memory precursory effector T cells; MAVS: mitochondrial antiviral signaling protein; NBR1: NBR1 autophagy cargo receptor; PI4KB/PI4KIIIβ: phosphatidylinositol 4-kinase beta; PLEKHM1: pleckstrin homology and RUN domain containing M1; RB1CC1: RB1 inducible coiled-coil 1; RTN3: reticulon 3; rIGSRNAs: ribosomal intergenic noncoding RNAs; RPL29: ribosomal protein L29; RPS3: ribosomal protein S3; ; sEV: small extracellular vesicles; ; SQSTM1: sequestosome 1; SF3B1: splicing factor 3b subunit 1; SILAC-MS: stable isotope labeling with amino acids in cell culture-mass spectrometry; SNAP29: synaptosome associated protein 29; TEX264: testis expressed 264, ER-phagy receptor; TNBC: triple-negative breast cancer; ULK1: unc-51 like autophagy activating kinase 1; VAS: Vancouver Autophagy Symposium.
Topics: Animals; Autophagy; Autophagy-Related Proteins; Disease; Humans; Proteome; Proteomics; Stress, Physiological
PubMed: 32507070
DOI: 10.1080/15548627.2020.1775394 -
Annals of Neurology Aug 2022Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), is a severe pediatric disorder of uncertain etiology resulting...
OBJECTIVE
Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), is a severe pediatric disorder of uncertain etiology resulting in hypothalamic dysfunction and frequent sudden death. Frequent co-occurrence of neuroblastic tumors have fueled suspicion of an autoimmune paraneoplastic neurological syndrome (PNS); however, specific anti-neural autoantibodies, a hallmark of PNS, have not been identified. Our objective is to determine if an autoimmune paraneoplastic etiology underlies ROHHAD.
METHODS
Immunoglobulin G (IgG) from pediatric ROHHAD patients (n = 9), non-inflammatory individuals (n = 100) and relevant pediatric controls (n = 25) was screened using a programmable phage display of the human peptidome (PhIP-Seq). Putative ROHHAD-specific autoantibodies were orthogonally validated using radioactive ligand binding and cell-based assays. Expression of autoantibody targets in ROHHAD tumor and healthy brain tissue was assessed with immunohistochemistry and mass spectrometry, respectively.
RESULTS
Autoantibodies to ZSCAN1 were detected in ROHHAD patients by PhIP-Seq and orthogonally validated in 7/9 ROHHAD patients and 0/125 controls using radioactive ligand binding and cell-based assays. Expression of ZSCAN1 in ROHHAD tumor and healthy human brain tissue was confirmed.
INTERPRETATION
Our results support the notion that tumor-associated ROHHAD syndrome is a pediatric PNS, potentially initiated by an immune response to peripheral neuroblastic tumor. ZSCAN1 autoantibodies may aid in earlier, accurate diagnosis of ROHHAD syndrome, thus providing a means toward early detection and treatment. This work warrants follow-up studies to test sensitivity and specificity of a novel diagnostic test. Last, given the absence of the ZSCAN1 gene in rodents, our study highlights the value of human-based approaches for detecting novel PNS subtypes. ANN NEUROL 2022;92:279-291.
Topics: Autoantibodies; Autonomic Nervous System Diseases; Child; Endocrine System Diseases; Humans; Hypothalamic Diseases; Hypoventilation; Ligands; Paraneoplastic Syndromes, Nervous System; Syndrome
PubMed: 35466441
DOI: 10.1002/ana.26380 -
Disease Models & Mechanisms Mar 2020Regulation of protein synthesis makes a major contribution to post-transcriptional control pathways. During disease, or under stress, cells initiate processes to... (Review)
Review
Regulation of protein synthesis makes a major contribution to post-transcriptional control pathways. During disease, or under stress, cells initiate processes to reprogramme protein synthesis and thus orchestrate the appropriate cellular response. Recent data show that the elongation stage of protein synthesis is a key regulatory node for translational control in health and disease. There is a complex set of factors that individually affect the overall rate of elongation and, for the most part, these influence either transfer RNA (tRNA)- and eukaryotic elongation factor 1A (eEF1A)-dependent codon decoding, and/or elongation factor 2 (eEF2)-dependent ribosome translocation along the mRNA. Decoding speeds depend on the relative abundance of each tRNA, the cognate:near-cognate tRNA ratios and the degree of tRNA modification, whereas eEF2-dependent ribosome translocation is negatively regulated by phosphorylation on threonine-56 by eEF2 kinase. Additional factors that contribute to the control of the elongation rate include epigenetic modification of the mRNA, coding sequence variation and the expression of eIF5A, which stimulates peptide bond formation between proline residues. Importantly, dysregulation of elongation control is central to disease mechanisms in both tumorigenesis and neurodegeneration, making the individual key steps in this process attractive therapeutic targets. Here, we discuss the relative contribution of individual components of the translational apparatus (e.g. tRNAs, elongation factors and their modifiers) to the overall control of translation elongation and how their dysregulation contributes towards disease processes.
Topics: Aminoacylation; Animals; Carcinogenesis; Disease; Health; Humans; Peptide Chain Elongation, Translational; RNA, Transfer
PubMed: 32298235
DOI: 10.1242/dmm.043208 -
Neurology India 2021Rise in intracranial tension (ICT) has varied clinical presentation which can range from subtle disturbances like headache to frank neurologic impairment. An important...
Rise in intracranial tension (ICT) has varied clinical presentation which can range from subtle disturbances like headache to frank neurologic impairment. An important aspect is rapidity of rise of ICT. Pseudotumor cerebri is associated with many syndromes, toxication, and drugs. Our case is a unique one given the rarity of eltroxin, which is otherwise relatively safe drug and commonly used in this part of the world, induced Pseudotumor cerebri. Our patient had dramatic response to discontinuation of levothyroxine.
Topics: Headache; Humans; Pseudotumor Cerebri; Syndrome; Thyroxine
PubMed: 34747819
DOI: 10.4103/0028-3886.329602 -
Cellular & Molecular Immunology Jun 2020In contrast to the previous belief that autoreactive B cells are eliminated from the normal repertoire of B cells, many autoreactive B cells actually escape clonal... (Review)
Review
In contrast to the previous belief that autoreactive B cells are eliminated from the normal repertoire of B cells, many autoreactive B cells actually escape clonal deletion and develop into mature B cells. These autoreactive B cells in healthy individuals perform some beneficial functions in the host and are homeostatically regulated by regulatory T and B cells or other mechanisms to prevent autoimmune diseases. Autoreactive B-1 cells constitutively produce polyreactive natural antibodies for tissue homeostasis. Recently, autoreactive follicular B cells were reported to participate actively in the germinal center reaction. Furthermore, the selection and usefulness of autoreactive marginal zone (MZ) B cells found in autoimmune diseases are not well understood, although the repertoire of MZ B-cell receptors (BCRs) is presumed to be biased to detect bacterial antigens. In this review, we discuss the autoreactive B-cell populations among all three major B-cell subsets and their regulation in immune responses and diseases.
Topics: Animals; Antibody Formation; B-Lymphocytes; Disease; Health; Homeostasis; Humans; Immunity
PubMed: 32382130
DOI: 10.1038/s41423-020-0445-4 -
RNA Biology May 2021The adaptive immune system is responsible for generating immunological response and immunological memory. Regulation of adaptive immunity including B cell and T cell... (Review)
Review
The adaptive immune system is responsible for generating immunological response and immunological memory. Regulation of adaptive immunity including B cell and T cell biology was mainly understood from the protein and microRNA perspective. However, long non-coding RNAs (lncRNAs) are an emerging class of non-coding RNAs (ncRNAs) that influence key factors in lymphocyte biology such as NOTCH, PAX5, MYC and EZH2. LncRNAs were described to modulate lymphocyte activation by regulating pathways such as NFAT, NFκB, MYC, interferon and TCR/BCR signalling (), and cell effector functions (). Here we review lncRNA involvement in adaptive immunity and the implications for autoimmune diseases (multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis) and T/B cell leukaemias and lymphomas (CLL, MCL, DLBCL, T-ALL). It is becoming clear that lncRNAs are important in adaptive immune response and provide new insights into its orchestration.
Topics: Adaptive Immunity; Animals; Disease; Humans; Lymphocyte Activation; RNA, Long Noncoding; Signal Transduction; T-Lymphocytes
PubMed: 33094664
DOI: 10.1080/15476286.2020.1838783 -
Pediatric Emergency Care Oct 2021Most children with coronavirus disease 2019 (COVID-19) infection are asymptomatic or have mild disease. About 5% of infected children will develop severe or critical... (Review)
Review
Most children with coronavirus disease 2019 (COVID-19) infection are asymptomatic or have mild disease. About 5% of infected children will develop severe or critical disease. Rapid identification and treatment are essential for children who are critically ill with signs and symptoms of respiratory failure, septic shock, and multisystem inflammatory syndrome in children. This article is intended for pediatricians, pediatric emergency physicians, and individuals involved in the emergency care of children. It reviews the current epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children, summarizes key aspects of clinical assessment including identification of high-risk patients and manifestations of severe disease, and provides an overview of COVID-19 management in the emergency department based on clinical severity.
Topics: COVID-19; Child; Emergency Service, Hospital; Humans; SARS-CoV-2; Syndrome; Systemic Inflammatory Response Syndrome
PubMed: 34591810
DOI: 10.1097/PEC.0000000000002538 -
Zeitschrift Fur Rheumatologie Sep 2020Autoinflammatory syndromes are characterized by periodic fever attacks in combination with increased inflammatory markers. The dysregulation of different cellular... (Review)
Review
Autoinflammatory syndromes are characterized by periodic fever attacks in combination with increased inflammatory markers. The dysregulation of different cellular signaling pathways leads to an excessive immune response which can in turn promote multisystemic inflammatory processes. Due to overlapping symptoms, variable expressivity, and pleiotropy, a purely clinical diagnosis of autoinflammatory diseases is difficult in many cases. Because an early and definitive diagnosis can greatly improve the quality of life of many patients, molecular genetic methods have become an important part of the diagnostic process. With the development of next-generation sequencing (NGS), the genetic diagnosis of patients with autoinflammatory diseases has improved significantly. Considerable progress has not only been made in the genetic characterization of undiagnosed patients, but additionally in identifying numerous new disease-associated genes. However, the plethora of molecular genetic analysis methods makes it difficult to select the method with the highest diagnostic specificity and sensitivity. The NGS technologies have led to a strong increase in the number of identified variants, making the clinical evaluation of these variants more complex. Consensus-driven and standardized molecular diagnostic guidelines, both for the diagnostic process and for the interpretation of the obtained results, have therefore become essential.
Topics: Biomarkers; Fever; Genetic Testing; Hereditary Autoinflammatory Diseases; Humans; Quality of Life; Syndrome
PubMed: 32761370
DOI: 10.1007/s00393-020-00847-7