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Objective: The neuropeptide calcitonin gene-related peptide (CGRP) has been established to be a key signaling molecule in migraine, but little is known about the differences between the two isoforms: αCGRP and βCGRP. Previous studies have been hampered by their close similarity, making the development of specific antibodies nearly impossible. In this study we sought to test the hypothesis that αCGRP and βCGRP localize differently within the neurons of the mouse trigeminal ganglion (TG), using αCGRP knock out (KO) animals. Methods: We applied immunohistochemistry (IHC) on 15 TGs from three different genotypes of mice; wild type (WT) αCGRP heterozygote (Het) and αCGRP KOs, with a primary antibody targeting the mature neuropeptide sequence of both αCGRP and βCGRP. Subsequently, the localization patterns of the two isoforms were analyzed. Furthermore, similar IHCs were produced in KO animals after being treated with monoclonal CGRP antibodies to study the origin of the observed CGRP. Additional IHCs were conducted in KO and WT mice to locate CGRP sorting peptides within neuronal cell bodies. Lastly, bioinformatical analyses of the primary, secondary, and tertiary structure of the two isoforms were conducted. Results: The IHC showed that the key isoform localized within the axons of the mouse TG neurons, is αCGRP and not βCGRP. Furthermore, differences in intensities indicate that the model used in this study successfully knocks out αCGRP. We further categorized the localization patterns of CGRP in neuronal cell bodies in the TG and found using bioinformatic analyses that differences in localization might be explained by intracellular peptide sorting. IHC following injections with monoclonal CGRP antibodies in KO mice ruled out the possibility that the βCGRP observed in trigeminal neurons had peripheral origins. This conclusion was enhanced by IHC experiments which showed the presence of CGRP co-localizing sorting peptides in KO mice. Conclusion: Our data show that mainly αCGRP and not βCGRP locate within the axons of the mouse TG neurons. The βCGRP observed within the TG neuronal cell bodies is synthesized intracellularly and not taken up from the environment. Furthermore, the isoforms appear to be sorted differentially into secretory vesicles in the cell bodies of TG neurons. [ABSTRACT FROM AUTHOR]

Mitochondria-endoplasmic reticulum contacts (MERCs), also called endoplasmic reticulum (ER)-mitochondria contact sites (ERMCS), are the membrane domains, where these two organelles exchange lipids, Ca2+ ions, and reactive oxygen species. This crosstalk is a major determinant of cell metabolism, since it allows the ER to control mitochondrial oxidative phosphorylation and the Krebs cycle, while conversely, it allows the mitochondria to provide sufficient ATP to control ER proteostasis. MERC metabolic signaling is under the control of tethers and a multitude of regulatory proteins. Many of these proteins have recently been discovered to give rise to rare diseases if their genes are mutated. Surprisingly, these diseases share important hallmarks and cause neurological defects, sometimes paired with, or replaced by skeletal muscle deficiency. Typical symptoms include developmental delay, intellectual disability, facial dysmorphism and ophthalmologic defects. Seizures, epilepsy, deafness, ataxia, or peripheral neuropathy can also occur upon mutation of a MERC protein. Given that most MERC tethers and regulatory proteins have secondary functions, some MERC protein-based diseases do not fit into this categorization. Typically, however, the proteins affected in those diseases have dominant functions unrelated to their roles in MERCs tethering or their regulation. We are discussing avenues to pharmacologically target genetic diseases leading to MERC defects, based on our novel insight that MERC defects lead to common characteristics in rare diseases. These shared characteristics of MERCs disorders raise the hope that they may allow for similar treatment options. [ABSTRACT FROM AUTHOR]

Objectives: The risk of intracranial aneurysms (IAs) development and rupture is significantly higher in patients with periodontitis (PD), suggesting an association between the two. However, the specific mechanisms of association between these two diseases have not been fully investigated. Materials and methods: In this study, we downloaded IAs and PD data from the Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified, and functional enrichment analysis was performed. The protein-protein interaction (PPI) network and weighted gene co-expression network analysis (WGCNA) was performed to identified key modules and key crosstalk genes. In addition, the immune cell landscape was assessed and the correlation of key crosstalk genes with each immune cell was calculated. Finally, transcription factors (TFs) regulating key crosstalk genes were explored. Results: 127 overlapping DEGs were identified and functional enrichment analysis highlighted the important role of immune reflection in the pathogenesis of IAs and PD. We identified ITGAX and COL4A2 as key crosstalk genes. In addition, the expression of multiple immune cells was significantly elevated in PDs and IAs compared to controls, and both key crosstalk genes were significantly negatively associated with Macrophages M2. Finally, GATA2 was identified as a potential key transcription factor (TF), which regulates two key crosstalk gene. Conclusions: The present study identifies key crosstalk genes and TF in PD and IAs, providing new insights for further study of the co-pathogenesis of PD and IAs from an immune and inflammatory perspective. Also, this is the first study to report the above findings. [ABSTRACT FROM AUTHOR]

Chronic HIV-1 infection is characterized by T-cell dysregulation that is partly restored by antiretroviral therapy. Autophagy is a critical regulator of T-cell function. Here, we demonstrate a protective role for autophagy in HIV-1 disease pathogenesis. Targeted analysis of genetic variation in core autophagy gene ATG16L1 reveals the previously unidentified rs6861 polymorphism, which correlates functionally with enhanced autophagy and clinically with improved survival of untreated HIV-1-infected individuals. T-cells carrying ATG16L1 rs6861(TT) genotype display improved antiviral immunity, evidenced by increased proliferation, revamped immune responsiveness, and suppressed exhaustion/immunosenescence features. In-depth flow-cytometric and transcriptional profiling reveal T-helper-cell-signatures unique to rs6861(TT) individuals with enriched regulation of pro-inflammatory networks and skewing towards immunoregulatory phenotype. Therapeutic enhancement of autophagy recapitulates the rs6861(TT)-associated T-cell traits in non-carriers. These data underscore the in vivo relevance of autophagy for longer-lasting T-cell-mediated HIV-1 control, with implications towards development of host-directed antivirals targeting autophagy to restore immune function in chronic HIV-1 infection. T cell dysregulation is a hallmark of chronic HIV-1 infection that is partially restored by antiretroviral therapy. Here the authors show that ATG16L1 rs6861 polymorphism is associated clinically with prolonged control of disease pathogenesis, and functionally with enhanced autophagy and T-cell immunity in chronically HIV-1 infected individuals. [ABSTRACT FROM AUTHOR]

In this work, we propose a morphologic analysis by means of the construction of 3D models of the SARS-CoV-2 VP (viral particles) with algorithms in Python and Matlab based on the processing of frames. To this aim, we simulate the Takeda method to induce periodicity and apply the Fourier transform to obtain the phase of objects under analysis. To this aim, we analyze several research works focused on infected tissues by SARS-CoV-2 virus culture cells, highlighting the obtained medical images of the virus from microscopy and tomography. We optimize the results by performing image processing (segmentation and periodic noise removal) in order to obtain an accurate ROI (Region of Interest) segmentation containing only information on SARS-CoV-2 cells. We apply our algorithm to these images (3D tomographic medical images) to simulate the Takeda method (which also filters the image), considering the periodicity induced by us in the image to carry out a phase unwrapping process. Finally, we use the image phase to focus on the body, center (RNA, Protein M-N), and spikes (Protein S) of the SARS-CoV-2 cells to identify them as characteristic elements of the SARS-CoV-2 virion morphology to build a 3D model based only in the metadata of clinical studies on cell cultures. The latter results in the construction of a mathematical, physical, biological, and numerical model of the SARS-CoV-2 virion, a tool with volumes, or 3D non-speculative or animated models, based only on medical images (3D tomography) in clinical tests, faithful to the virus. [ABSTRACT FROM AUTHOR]

Blood-brain barrier (BBB) breakdown is one of the pathophysiological characteristics of ischemic stroke, which may contribute to the progression of brain tissue damage and subsequent neurological impairment. Human immunodeficiency virus (HIV)-infected individuals are at greater risk for ischemic stroke due to diminished immune function and HIV-associated vasculopathy. Studies have shown that astrocytes are involved in maintaining BBB integrity and facilitating HIV-1 infection in the brain. The present study investigated whether targeting astrocyte-endothelial cell signaling with cenicriviroc (CVC), a dual chemokine receptor (CCR)2 and CCR5 antagonist, may protect against dysregulation of cross talk between these cells after oxygen-glucose deprivation/reoxygenation (OGD/R) combined with HIV-1 infection. Permeability assay with 10 kDa fluorescein isothiocyanate (FITC)-dextran demonstrated that CVC alleviated endothelial barrier disruption in noncontact coculture of human brain microvascular endothelial cells (HBMECs) with HIV-1-infected human astrocytes, and reversed downregulation of tight junction protein claudin-5 induced by OGD/R- and HIV-1. Moreover, CVC attenuated OGD/R- and HIV-1-triggered upregulation of the NOD-like receptor protein-3 (NLRP3) inflammasome and IL-1β secretion. Treatment with CVC also suppressed astrocyte pyroptosis by attenuating cleaved caspase-1 levels and the formation of cleaved N-terminal GSDMD (N-GSDMD). Secretome profiling revealed that CVC ameliorated secretion levels of chemokine CC chemokine ligand 17 (CCL17), adhesion molecule intercellular adhesion molecule-1 (ICAM-1), and T cell activation modulator T cell immunoglobulin and mucin domain 3 (TIM-3) by astrocytes synergistically induced by OGD/R and HIV-1. Overall, these results suggest that CVC contributes to restoring astrocyte-endothelial cross interactions in an astrocyte-dependent manner via protection against NLRP3 activation and pyroptosis. NEW & NOTEWORTHY The present study reveals the role of astrocytic NOD-like receptor protein-3 (NLRP3) inflammasome in dysfunctional astrocyte-endothelial cross interactions triggered in response to oxygen/glucose deprivation injury associated with human immunodeficiency virus type 1 (HIV-1) infection. Our results suggest that blocking NLRP3 inflammasome activation and pyroptosis-mediated inflammation with cenicriviroc (CVC) may constitute a potentially effective therapeutic strategy for bloodbrain barrier (BBB) protection during HIV-1-associated ischemic stroke. [ABSTRACT FROM AUTHOR]

PACS1 syndrome is a neurodevelopmental disorder characterized by intellectual disability and distinct craniofacial abnormalities resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). PACS1 is known to have functions in the endosomal pathway and nucleus, but how the p.R203W variant affects developing neurons is not fully understood. Here we differentiated stem cells towards neuronal models including cortical organoids to investigate the impact of the PACS1 syndrome-causing variant on neurodevelopment. While few deleterious effects were detected in PACS1(+/R203W) neural precursors, mature PACS1(+/R203W) glutamatergic neurons exhibited impaired expression of genes involved in synaptic signaling processes. Subsequent characterization of neural activity using calcium imaging and multielectrode arrays revealed the p.R203W PACS1 variant leads to a prolonged neuronal network burst duration mediated by an increased interspike interval. These findings demonstrate the impact of the PACS1 p.R203W variant on developing human neural tissue and uncover putative electrophysiological underpinnings of disease. PACS1 syndrome is a neurodevelopmental disorder resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). Here the authors use cortical organoids to investigate the impact of this variant on neurodevelopment. [ABSTRACT FROM AUTHOR]

This document provides a list of references to scientific articles and studies related to the treatment of COVID-19. The studies cover various topics, including the use of convalescent plasma, monoclonal antibodies, antiviral drugs, and immune modulators in COVID-19 treatment. The document allows researchers to access the full text of the articles for further information on these treatment strategies. [Extracted from the article]

COVID-19 continues to affect an unprecedented number of people with the emergence of new variants posing a serious challenge to global health. There is an expansion of knowledge in understanding the pathogenesis of Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the impact of the acute disease on multiple organs. In addition, growing evidence reports that the impact of COVID-19 on different organs persists long after the recovery phase of the disease, leading to long-term consequences of COVID-19. These long-term consequences involve pulmonary as well as extra-pulmonary sequelae of the disease. Noteably, recent research has shown a potential association between COVID-19 and change in the molecular cargo of extracellular vesicles (EVs). EVs are vesicles released by cells and play an important role in cell communication by transfer of bioactive molecules between cells. Emerging evidence shows a strong link between EVs and their molecular cargo, and regulation of metabolism in health and disease. This review focuses on current knowledge about EVs and their potential role in COVID-19 pathogenesis, their current and future implications as tools for biomarker and therapeutic development and their possible effects on long-term impact of COVID-19. [ABSTRACT FROM AUTHOR]

During mitotic entry of vertebrate cells, nuclear pore complexes (NPCs) are rapidly disintegrated. NPC disassembly is initiated by hyperphosphorylation of linker nucleoporins (Nups), which leads to the dissociation of FG repeat Nups and relaxation of the nuclear permeability barrier. However, less is known about disintegration of the huge nuclear and cytoplasmic rings, which are formed by annular assemblies of Y‐complexes that are dissociated from NPCs as intact units. Surprisingly, we observe that Y‐complex Nups display slower dissociation kinetics compared with other Nups during in vitro NPC disassembly, indicating a mechanistic difference in the disintegration of Y‐based rings. Intriguingly, biochemical experiments reveal that a fraction of Y‐complexes remains associated with mitotic ER membranes, supporting recent microscopic observations. Visualization of mitotic Y‐complexes by super‐resolution microscopy demonstrates that they form two classes of higher order assemblies: large clusters at kinetochores and small, focal ER‐associated assemblies. These, however, lack features qualifying them as persisting ring‐shaped subassemblies previously proposed to serve as structural templates for NPC reassembly during mitotic exit, which helps to refine current models of nuclear reassembly. Synopsis: The outer NPC scaffold is built by rings of Y‐complexes. Whereas the bulk of Y‐complexes is solubilized during mitosis, a fraction of Y‐complexes is found in association with the mitotic ER network where they are organized in form of small focal assemblies that lack features of NPC rings. Y‐complex Nups display distinct dissociation kinetics during NPC disassembly in vitro.10–20% of Y‐complexes associate with the mitotic ER network.dSTORM microscopy reveals that ER‐associated Y‐complexes form small foci instead of ring‐shaped structures suited for templated NPC reassembly. [ABSTRACT FROM AUTHOR]

Background: Despite widespread study of dendritic cell (DC)-based cancer immunotherapies, the in vivo postinjection fate of DC remains largely unknown. Due in part to a lack of quantifiable imaging modalities, this is troubling as the amount of DC migration to secondary lymphoid organs correlates with therapeutic efficacy. Magnetic particle imaging (MPI) has emerged as a suitable modality to quantify in vivo migration of superparamagnetic iron oxide (SPIO)-labeled DC. Herein, we describe a popliteal lymph node (pLN)-focused MPI scan to quantify DC in vivo migration accurately and consistently. Methods: Adenovirus (Ad)-transduced SPIO+ (Ad SPIO+) and SPIO+ C57BL/6 bone marrow-derived DC were generated and assessed for viability and phenotype, then fluorescently labeled and injected into mouse hind footpads (n = 6). Two days later, in vivo DC migration was quantified using whole animal, pLN-focused, and ex vivo pLN MPI scans. Results: No significant differences in viability, phenotype and in vivo pLN migration were noted for Ad SPIO+ and SPIO+ DC. Day 2 pLN-focused MPI quantified DC migration in all instances while whole animal MPI only quantified pLN migration in 75% of cases. Ex vivo MPI and fluorescence microscopy confirmed that pLN MPI signal was due to originally injected Ad SPIO+ and SPIO+ DC. Conclusion: We overcame a reported limitation of MPI by using a pLN-focused MPI scan to quantify pLN-migrated Ad SPIO+ and SPIO+ DC in 100% of cases and detected as few as 1000 DC (4.4 ng Fe) in vivo. MPI is a suitable preclinical imaging modality to assess DC-based cancer immunotherapeutic efficacy. Relevance statement: Tracking the in vivo fate of DC using noninvasive quantifiable magnetic particle imaging can potentially serve as a surrogate marker of therapeutic effectiveness. Key points: • Adenoviral-transduced and iron oxide-labeled dendritic cells are in vivo migration competent. • Magnetic particle imaging is a suitable modality to quantify in vivo dendritic cell migration. • Magnetic particle imaging focused field of view overcomes dynamic range limitation. [ABSTRACT FROM AUTHOR]

Nef is an accessory protein unique to the primate HIV-1, HIV-2, and SIV lentiviruses. During infection, Nef functions by interacting with multiple host proteins within infected cells to evade the immune response and enhance virion infectivity. Notably, Nef can counter immune regulators such as CD4 and MHC-I, as well as the SERINC5 restriction factor in infected cells. In this study, we generated a posterior sample of time-scaled phylogenies relating SIV and HIV Nef sequences, followed by reconstruction of ancestral sequences at the root and internal nodes of the sampled trees up to the HIV-1 Group M ancestor. Upon expression of the ancestral primate lentivirus Nef protein within CD4 + HeLa cells, flow cytometry analysis revealed that the primate lentivirus Nef ancestor robustly downregulated cell-surface SERINC5, yet only partially downregulated CD4 from the cell surface. Further analysis revealed that the Nef-mediated CD4 downregulation ability evolved gradually, while Nef-mediated SERINC5 downregulation was recovered abruptly in the HIV-1/M ancestor. Overall, this study provides a framework to reconstruct ancestral viral proteins and enable the functional characterization of these proteins to delineate how functions could have changed throughout evolutionary history. [ABSTRACT FROM AUTHOR]

The success of many current vaccines relies on a formulation that incorporates an immune activating adjuvant. This will hold true for the design of a successful therapeutic HIV vaccine targeted at controlling reactivated virus following cessation of combined antiretroviral therapy (cART). The HIV accessory protein Nef functions by interfering with HIV antigen presentation through the major histocompatibility complex I (MHC-I) pathway thereby suppressing CD8+ cytotoxic T cell (CTL)-mediated killing of HIV infected cells. Thus, this important impediment to HIV vaccine success must be circumvented. This review covers our current knowledge of Nef inhibitors that may serve as immune adjuvants that will specifically restore and enhance CTL-mediated killing of reactivated HIV infected cells as part of an overall vaccine strategy to affect a cure for HIV infection. [ABSTRACT FROM AUTHOR]

Mucosa-associated invariant T (MAIT) cells are MR1-restricted, innate-like T lymphocytes with tremendous antibacterial and immunomodulatory functions. Additionally, MAIT cells sense and respond to viral infections in an MR1-independent fashion. However, whether they can be directly targeted in immunization strategies against viral pathogens is unclear. We addressed this question in multiple wild-type and genetically altered but clinically relevant mouse strains using several vaccine platforms against influenza viruses, poxviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We demonstrate that 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a riboflavin-based MR1 ligand of bacterial origin, can synergize with viral vaccines to expand MAIT cells in multiple tissues, reprogram them towards a pro-inflammatory MAIT1 phenotype, license them to bolster virus-specific CD8+ T cell responses, and potentiate heterosubtypic anti-influenza protection. Repeated 5-OP-RU administration did not render MAIT cells anergic, thus allowing for its inclusion in prime-boost immunization protocols. Mechanistically, tissue MAIT cell accumulation was due to their robust proliferation, as opposed to altered migratory behavior, and required viral vaccine replication competency and Toll-like receptor 3 and type I interferon receptor signaling. The observed phenomenon was reproducible in female and male mice, and in both young and old animals. It could also be recapitulated in a human cell culture system in which peripheral blood mononuclear cells were exposed to replicating virions and 5-OP-RU. In conclusion, although viruses and virus-based vaccines are devoid of the riboflavin biosynthesis machinery that supplies MR1 ligands, targeting MR1 enhances the efficacy of vaccine-elicited antiviral immunity. We propose 5-OP-RU as a non-classic but potent and versatile vaccine adjuvant against respiratory viruses. Author summary: Mucosa-associated invariant T (MAIT) cells are evolutionarily conserved lymphocytes that recognize and respond to bacterial metabolites presented by an antigen-presenting molecule called MR1. Although MAIT cells have been implicated in antiviral immunity, whether their stimulation by MR1 ligands can improve immune responses to viral invaders has been unclear. We addressed this question in several mouse models and primary and prime-boost immunization strategies against influenza viruses, poxviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We demonstrate that an MR1 ligand called 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) can be incorporated into select vaccine formulations to expand tissue MAIT cells and reprogram them towards a pro-inflammatory phenotype, to enhance conventional virus-specific T cell responses, and to promote protection against influenza A viruses (IAVs). We found this phenomenon to be dependent upon the in vivo engagement of a pathogen recognition receptor called Toll-like receptor 3 as well as the receptor for type I interferons. Also importantly, MAIT cell proliferation in response to an IAV strain and 5-OP-RU could be phenocopied in a human white blood cell culture system. We propose that 5-OP-RU, and potentially other MR1 ligands, may be used to increase the efficacy of certain vaccines against respiratory viral infections. [ABSTRACT FROM AUTHOR]

Arsenic is a known human carcinogen. Low doses of arsenic can induce cell proliferation, but the mechanism remains elusive. Aerobic glycolysis, also known as the Warburg effect, is one of the characteristics of tumour cells and rapidly proliferating cells. P53 is a tumour suppressor gene that has been shown to be a negative regulator of aerobic glycolysis. SIRT1 is a deacetylase that inhibits the function of P53. In this study, we found that P53 was involved in low dose of arsenic-induced aerobic glycolysis through regulating HK2 expression in L-02 cells. Moreover, SIRT1 not only inhibited P53 expression but also decreased the acetylation level of P53-K382 in arsenic-treated L-02 cells. Meanwhile, SIRT1 influenced the expression of HK2 and LDHA, which then promoted arsenic-induced glycolysis in L-02 cells. Therefore, our study demonstrated that the SIRT1/P53 pathway is involved in arsenic-induced glycolysis, thereby promoting cell proliferation, which provides theoretical basis for enriching the mechanism of arsenic carcinogenesis. [ABSTRACT FROM AUTHOR]

ICA512/PTPRN is a receptor tyrosine‐like phosphatase implicated in the biogenesis and turnover of the insulin secretory granules (SGs) in pancreatic islet beta cells. Previously we found biophysical evidence that its luminal RESP18 homology domain (RESP18HD) forms a biomolecular condensate and interacts with insulin in vitro at close‐to‐neutral pH, that is, in conditions resembling those present in the early secretory pathway. Here we provide further evidence for the relevance of these findings by showing that at pH 6.8 RESP18HD interacts also with proinsulin—the physiological insulin precursor found in the early secretory pathway and the major luminal cargo of β‐cell nascent SGs. Our light scattering analyses indicate that RESP18HD and proinsulin, but also insulin, populate nanocondensates ranging in size from 15 to 300 nm and 10e2 to 10e6 molecules. Co‐condensation of RESP18HD with proinsulin/insulin transforms the initial nanocondensates into microcondensates (size >1 μm). The intrinsic tendency of proinsulin to self‐condensate implies that, in the ER, a chaperoning mechanism must arrest its spontaneous intermolecular condensation to allow for proper intramolecular folding. These data further suggest that proinsulin is an early driver of insulin SG biogenesis, in a process in which its co‐condensation with RESP18HD participates in their phase separation from other secretory proteins in transit through the same compartments but destined to other routes. Through the cytosolic tail of ICA512, proinsulin co‐condensation with RESP18HD may further orchestrate the recruitment of cytosolic factors involved in membrane budding and fission of transport vesicles and nascent SGs. [ABSTRACT FROM AUTHOR]

Group A Streptococcus (GAS, Streptococcus pyogenes) is a professional human pathogen that commonly infects the skin. Keratinocytes are one of the first cells to contact GAS, and by inducing inflammation, they can initiate the earliest immune responses to pathogen invasion. Here, we characterized the proinflammatory cytokine repertoire produced by primary human keratinocytes and surrogate cell lines commonly used in vitro. Infection induces several cytokines and chemokines, but keratinocytes constitutively secrete IL-18 in a form that is inert (pro-IL-18) and lacks proinflammatory activity. Canonically, IL-18 activation and secretion are coupled through a single proteolytic event that is regulated intracellularly by the inflammasome protease caspase-1 in myeloid cells. The pool of extracellular pro-IL-18 generated by keratinocytes is poised to sense extracellular proteases. It is directly processed into a mature active form by SpeB, a secreted GAS protease that is a critical virulent factor during skin infection. This mechanism contributes to the proinflammatory response against GAS, resulting in T cell activation and the secretion of IFN-γ. Under these conditions, isolates of several other major bacterial pathogens and microbiota of the skin were found to not have significant IL-18-maturing ability. These results suggest keratinocyte-secreted IL-18 is a sentinel that sounds an early alarm that is highly sensitive to GAS, yet tolerant to non-invasive members of the microbiota. Author summary: Timely and appropriate inflammation is critical for an effective immune response against an invading pathogen. Some immune effectors are stored in an inert form that is enzymatically activated. This can allow for responses much more rapidly than transcriptionally regulation, on the order of minutes. An important regulator of these rapid responses is the inflammasome, which among its activities, processes the proinflammatory cytokines IL-1β and IL-18 into truncated forms that gain the ability to bind their cognate receptors. These cytokines are typically stored intracellularly until activation, but human keratinocytes constitutively secrete IL-18 in its unprocessed form. We show that this pool of IL-18 initiates an immune response to the human pathogen group A Streptococcus, but not non-pathogens. Mechanistically, this occurs from IL-18 cleavage by SpeB, a major virulence factor that is required for tissue invasion. Keratinocytes live in close association with diverse microbes and face a challenge in selectively responding to pathogens while tolerating normal microbiota. Our findings outline a strategy for discriminating species with high virulence potential through their use of proteolytic virulence factors and IL-18 as bait. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdVs) are a large family of DNA viruses counting more than a hundred strains divided into seven species (A to G). HAdVs induce respiratory tract infections, gastroenteritis and conjunctivitis. APOBEC3B is a cytidine deaminase that restricts several DNA viruses. APOBEC3B is also implicated in numerous cancers where it is responsible for the introduction of clustered mutations into the cellular genome. In this study, we demonstrate that APOBEC3B is an adenovirus restriction factor acting through a deaminase-dependent mechanism. APOBEC3B introduces C-to-T clustered mutations into the adenovirus genome. APOBEC3B reduces the propagation of adenoviruses by limiting viral genome replication, progression to late phase, and production of infectious virions. APOBEC3B restriction efficiency varies between adenoviral strains, the A12 strain being more sensitive to APOBEC3B than the B3 or C2 strains. In A12-infected cells, APOBEC3B clusters in the viral replication centers. Importantly, we show that adenovirus infection leads to a reduction of the quantity and/or enzymatic activity of the APOBEC3B protein depending on the strains. The A12 strain seems less able to resist APOBEC3B than the B3 or C2 strains, a characteristic which could explain the strong depletion of the APOBEC3-targeted motifs in the A12 genome. These findings suggest that adenoviruses evolved different mechanisms to antagonize APOBEC3B. Elucidating these mechanisms could benefit the design of cancer treatments. This study also identifies adenoviruses as triggers of the APOBEC3B-mediated innate response. The involvement of certain adenoviral strains in the genesis of the APOBEC3 mutational signature observed in tumors deserves further study. Author summary: The APOBEC3B protein is overexpressed in many human tumors and promotes genetic diversity and resistance to drug and oncolytic viruses. The identification of the mechanisms that lead to the dysregulation of APOBEC3B and the search for ways to abrogate its expression in tumors are intensively pursued. We have previously shown that adenoviral infection triggers APOBEC3B expression. In this study, we demonstrate that APOBEC3B mutates the genome of adenoviruses during their replication in the nucleus. These results warrant further investigation of the role of adenoviruses in APOBEC3B dysregulation. Our study also suggests that adenoviruses have evolved mechanisms to antagonize APOBEC3B and that some adenoviral strains are highly capable of decreasing the amount of APOBEC3B protein in infected cells. Identification of the viral proteins involved could be used to design better oncolytic vectors capable of propagating in tumor cells expressing high levels of APOBEC3B. [ABSTRACT FROM AUTHOR]

The Drosophila melanogaster (fruit fly), is a crucial and straightforward model organism for researching how genetic changes affect behavior and neural activity. Drosophila is used by biologists to study the nervous system because of its genetic tractability, well-known complex behaviors, straightforward neuroanatomy, and numerous human genes orthologs. Due to the Drosophila central nervous system's diminutive size, neurochemical studies are difficult. Recently, electrochemistry-based techniques have been created to monitor the release and clearance of neurotransmitters in real time in both larvae and adults. So, in this study Drosophila models used to study neuromodulator activity were reviewed and compiled using various databases. It is possible to take a close look at the functional role of traditional neuromodulators like octopamine, serotonin, dopamine, and neuropeptides using the genetic toolkit of Drosophila. This study compiles neurotransmitter role such as dopamine, serotonin, and octopamine production in both genetically normal and mutant flies. The fly is a system that is well-suited to shed new light on the complex issue of how neuromodulation might link behavioral demands particular to a given scenario with the level of arousal in the brain. The fly has powerful genetic tools and increasingly well-defined behavioral circuits. [ABSTRACT FROM AUTHOR]

To present a literature review on various immunopathologic dysfunctions following COVID-19 infection and their potential implications in development of rhino-orbital-cerebral mucormycosis (ROCM). A literature search was performed via Google Scholar and PubMed with subsequent review of the accompanying references. Analogies were drawn between the immune and physiologic deviations caused by COVID-19 and the tendency of the same to predispose to ROCM. Sixty-two articles were reviewed. SARS-CoV-2 virus infection leads to disruption of epithelial integrity in the respiratory passages, which may be a potential entry point for the ubiquitous Mucorales to become invasive. COVID-19 related GRP78 protein upregulation may aid in spore germination and hyphal invasion by Mucorales. COVID-19 causes interference in macrophage functioning by direct infection, a tendency for hyperglycemia, and creation of neutrophil extracellular traps. This affects innate immunity against Mucorales. Thrombocytopenia and reduction in the number of natural killer (NK) cells and infected dendritic cells is seen in COVID-19. This reduces the host immune response to pathogenic invasion by Mucorales. Cytokines released in COVID-19 cause mitochondrial dysfunction and accumulation of reactive oxygen species, which cause oxidative damage to the leucocytes. Hyperferritinemia also occurs in COVID-19 resulting in suppression of the hematopoietic proliferation of B- and T-lymphocytes. COVID-19 has a role in the occurrence of ROCM due to its effects at the entry point of the fungus in the respiratory mucosa, effects of the innate immune system, creation of an environment of iron overload, propagation of hyperglycemia, and effects on the adaptive immune system. [ABSTRACT FROM AUTHOR]

Advances in structural analysis by cryogenic electron microscopy (cryo-EM) and X-ray crystallography have revealed the tertiary structures of various chromatin-related proteins, including transcription factors, RNA polymerases, nucleosomes, and histone chaperones; however, the dynamic structures of intrinsically disordered regions (IDRs) in these proteins remain elusive. Recent studies using nuclear magnetic resonance (NMR), together with molecular dynamics (MD) simulations, are beginning to reveal dynamic structures of the general transcription factor TFIIH complexed with target proteins including the general transcription factor TFIIE, the tumor suppressor p53, the cell cycle protein DP1, the DNA repair factors XPC and UVSSA, and three RNA polymerases, in addition to the dynamics of histone tails in nucleosomes and histone chaperones. In complexes of TFIIH, the PH domain of the p62 subunit binds to an acidic string formed by the IDR in TFIIE, p53, XPC, UVSSA, DP1, and the RPB6 subunit of three RNA polymerases by a common interaction mode, namely extended string-like binding of the IDR on the positively charged surface of the PH domain. In the nucleosome, the dynamic conformations of the N-tails of histones H2A and H2B are correlated, while the dynamic conformations of the N-tails of H3 and H4 form a histone tail network dependent on their modifications and linker DNA. The acidic IDRs of the histone chaperones of FACT and NAP1 play important roles in regulating the accessibility to histone proteins in the nucleosome. [ABSTRACT FROM AUTHOR]

The precise interaction between the immune system and severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is critical in deciphering the pathogenesis of coronavirus disease 2019 (COVID‐19) and is also vital for developing novel therapeutic tools, including monoclonal antibodies, antivirals drugs, and vaccines. Viral infections need innate and adaptive immune reactions since the various immune components, such as neutrophils, macrophages, CD4+ T, CD8+ T, and B lymphocytes, play different roles in various infections. Consequently, the characterization of innate and adaptive immune reactions toward SARS‐CoV‐2 is crucial for defining the pathogenicity of COVID‐19. In this study, we explain what is currently understood concerning the conventional immune reactions to SARS‐CoV‐2 infection to shed light on the protective and pathogenic role of immune response in this case. Also, in particular, we investigate the in‐depth roles of other immune mediators, including neutrophil elastase, serum amyloid A, and syndecan, in the immunopathogenesis of COVID‐19. [ABSTRACT FROM AUTHOR]

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Previous reports have confirmed the significance of CD93 in the progression of multiple tumors; however, there are few studies examining its immune properties for gliomas. Here, we methodically investigated the pathophysiological characteristics and clinical manifestations of gliomas. Six hundred ninety-nine glioma patients in TCGA along with 325 glioma patients in CGGA were correspondingly collected for training and validating. We analyzed and visualized total statistics using RStudio. One-way ANOVA and Student's t-test were used to assess groups' differences. All differences were considered statistically significant at the level of P < 0.05. CD93 markedly upregulated among HGG, MGMT promoter unmethylated subforms, IDH wild forms, 1p19q non-codeletion subforms, and mesenchyme type gliomas. ROC analysis illustrated the favorable applicability of CD93 in estimating mesenchyme subform. Kaplan–Meier curves together with multivariable Cox analyses upon survivance identified high-expression CD93 as a distinct prognostic variable for glioma patients. GO analysis of CD93 documented its predominant part in glioma-related immunobiological processes and inflammation responses. We examined the associations of CD93 with immune-related meta-genes, and CD93 positively correlated with HCK, LCK, MHC I, MHC II, STAT1 and IFN, while adverse with IgG. Association analyses between CD93 and gliomas-infiltrating immunocytes indicated that the infiltrating degrees of most immunocytes exhibited positive correlations with CD93, particularly these immunosuppressive subsets such as TAM, Treg, and MDSCs. CD93 is markedly associated with adverse pathology types, unfavorable survival, and immunosuppressive immunocytes infiltration among gliomas, thus identifying CD93 as a practicable marker and a promising target for glioma-based precise diagnosis and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Efferocytosis is the process by which apoptotic cells are removed without inflammation to maintain tissue homeostasis, prevent unwanted inflammatory responses, and inhibit autoimmune responses. Coordination of efferocytosis occurs via many surfaces and chemotactic molecules and adaptors. Recently, soluble positive or negative mediators of efferocytosis, have been more noticeable as non-invasive valuable biomarkers in prognosis and targeted therapy. These soluble factors can be detected in different bodily fluids, such as serum, plasma, and urine as a non-invasive method. There are lots of studies that have tried to show the importance of receptors and ligands in disorders; while a few studies tried to indicate the importance of soluble forms of receptors/ligands and their clinical aspects as a systemic compound and shedding of targets related to efferocytosis. Some of these soluble forms also can be as sensitive as specific biomarkers for certain diseases compared with routine biomarkers, such as soluble circulatory Lectin-like oxidized low-density lipoprotein receptor-1 vs. troponin T in the acute coronary syndrome. Thus, this review tried to gain more understanding about efferocytosis-related unwanted soluble receptors/ligands, their roles, the clinical significance, and potential for diagnosis, and prognosis related to different diseases. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies (GWASs) have identified multiple risk loci for bipolar disorder (BD). However, pinpointing functional (or causal) variants in the reported risk loci and elucidating their regulatory mechanisms remain challenging. Methods: We first integrated chromatin immunoprecipitation sequencing (ChIP-Seq) data from human brain tissues (or neuronal cell lines) and position weight matrix (PWM) data to identify functional single-nucleotide polymorphisms (SNPs). Then, we verified the regulatory effects of these transcription factor (TF) binding–disrupting SNPs (hereafter referred to as "functional SNPs") through a series of experiments, including reporter gene assays, allele-specific expression (ASE) analysis, TF knockdown, CRISPR/Cas9-mediated genome editing, and expression quantitative trait loci (eQTL) analysis. Finally, we overexpressed PACS1 (whose expression was most significantly associated with the identified functional SNPs rs10896081 and rs3862386) in mouse primary cortical neurons to investigate if PACS1 affects dendritic spine density. Results: We identified 16 functional SNPs (in 9 risk loci); these functional SNPs disrupted the binding of 7 TFs, for example, CTCF and REST binding was frequently disrupted. We then identified the potential target genes whose expression in the human brain was regulated by these functional SNPs through eQTL analysis. Of note, we showed dysregulation of some target genes of the identified TF binding–disrupting SNPs in BD patients compared with controls, and overexpression of PACS1 reduced the density of dendritic spines, revealing the possible biological mechanisms of these functional SNPs in BD. Conclusions: Our study identifies functional SNPs in some reported risk loci and sheds light on the regulatory mechanisms of BD risk variants. Further functional characterization and mechanistic studies of these functional SNPs and candidate genes will help to elucidate BD pathogenesis and develop new therapeutic approaches and drugs. [ABSTRACT FROM AUTHOR]

There is growing recognition of the diversity of viruses that can infect the cells of the central nervous system (CNS). While the majority of CNS infections are successfully cleared by the immune response, some viral infections persist in the CNS. As opposed to resolved infections, persistent viruses can contribute to ongoing tissue damage and neuroinflammatory processes. In this manuscript, we provide an overview of the current understanding of factors that lead to viral persistence in the CNS including how viruses enter the brain, how these pathogens evade antiviral immune system responses, and how viruses survive and transmit within the CNS. Further, as the CNS may serve as a unique viral reservoir, we examine the ways in which persistent viruses in the CNS are being targeted therapeutically. [ABSTRACT FROM AUTHOR]

Background: Atherosclerosis emerges as a result of multiple dynamic cell processes including endothelial damage, inflammatory and immune cell infiltration, foam cell formation, plaque rupture, and thrombosis. Animal experiments have indicated that cathepsins (CTSs) mediate the antigen transmission and inflammatory response involved in the atherosclerosis process, but the specific signal pathways and target cells of the CTSs involved in atherosclerosis are unknown. Methods: We used the GEO query package to download the dataset GSE28829 from the Gene Expression Omnibus (GEO) and filtered the data to check the standardization of the samples through the box chart. We then used the 'limma' package to analyze between-group differences and selected the corresponding differentially expressed genes of CTSs from the protein-protein interaction (PPI) network constructed with the STRING database, and then visualized the CTS-target genes. The best matching pathway and target cells were verified by a male mouse ligation experiment, single-sample GSEA (ssGSEA) analysis, and vitro experiment. Results: There were 275 differentially expressed genes (DEGs) selected from the GSE28829 dataset, and the DEGs were identified mainly in the PPI network; 58 core genes (APOE, CD74, CP, AIF1, etc.) target three selected CTS family members (CTSS, CTSB, and CTSC). After the enriched analysis, 15 CTS-target genes were markedly enriched in the phagosome signaling pathway. The mouse experiment results revealed that the percentages and numbers of monocytes and neutrophils and the number of CD68+ cells in CTSS deficiency (CatS-/-) group were lower than those in the wildtype (CatS+/+) group. CTSS mediating phagosome via macrophage were further verified by ssGSEA analysis and vitro experiment. Conclusions: CTSS are the main target molecules in the CTS family that are involved in atherosclerosis. The molecule participate in the progression of atherosclerosis by mediating the phagosome via macrophage. [ABSTRACT FROM AUTHOR]

Phosphofurin acidic cluster sorting protein 1 (PACS‐1) is canonically a cytosolic trafficking protein, yet recent reports have described nuclear roles for PACS‐1. Herein, we sought to define the nuclear transport mechanism of PACS‐1. We demonstrate that PACS‐1 nucleocytoplasmic trafficking is dependent on its interaction with the nuclear transport receptors importin alpha 5 and exportin 1. PACS‐1 nuclear entry and exit are defined by a nuclear localization signal (NLS, residues 311‐318) and nuclear export signal (NES3, residues 366‐375). Mutation of the PACS‐1 NLS and NES3 altered the localization of a complex formed between PACS‐1 and an RNA‐binding protein, polypyrimidine tract‐binding protein 1. Overall, we identify the nuclear localization mechanism of PACS‐1 and highlight a potential role for PACS‐1 in RNA‐binding protein trafficking. [ABSTRACT FROM AUTHOR]

Copyright of Virologie is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Peptide hormones are first produced as larger precursor prohormones that require endoproteolytic cleavage to liberate the mature hormones. A structurally conserved but functionally distinct family of nine prohormone convertase enzymes (PCs) are responsible for cleavage of protein precursors, of which PC1/3 and PC2 are known to be exclusive to neuroendocrine cells and responsible for prohormone cleavage. Differential expression of PCs within tissues defines prohormone processing; whereas glucagon is the major product liberated from proglucagon via PC2 in pancreatic a-cells, proglucagon is preferentially processed by PC1/3 in intestinal L cells to produce glucagon-like peptides 1 and 2 (GLP-1, GLP-2). Beyond our understanding of processing of islet prohormones in healthy islets, there is convincing evidence that proinsulin, pro-islet amyloid polypeptide (proIAPP), and proglucagon processing is altered during prediabetes and diabetes. There is predictive value of elevated circulating proinsulin or proinsulin-to-C-peptide ratio for progression to type 2 diabetes, and elevated proinsulin or proinsulin-to-C-peptide ratio is predictive for development of type 1 diabetes in at-risk groups. After onset of diabetes, patients have elevated circulating proinsulin and proIAPP, and proinsulin may be an autoantigen in type 1 diabetes. Furthermore, preclinical studies reveal that a-cells have altered proglucagon processing during diabetes, leading to increased GLP-1 production. We conclude that despite strong associative data, current evidence is inconclusive on the potential causal role of impaired prohormone processing in diabetes and suggest that future work should focus on resolving the question of whether altered prohormone processing is a causal driver or merely a consequence of diabetes pathology. [ABSTRACT FROM AUTHOR]

Background: Whether dysregulated iron metabolism is associated with COVID‐19‐associated mucormycosis (CAM) remains unknown. Herein, we compare the serum iron indices in COVID‐19 subjects with and without mucormycosis. Methods: We conducted a case–control study enrolling COVID‐19 participants with and without mucormycosis. We compared the baseline serum iron indices (iron, ferritin, total iron‐binding capacity [TIBC], unsaturated iron‐binding capacity and percentage transferrin saturation) between CAM cases and COVID‐19 controls. Additionally, we performed a multivariate logistic regression analysis to assess whether any iron indices are associated with CAM. Results: We enrolled 28 CAM cases (mean age 53.6 years old; 78.6% men) and 26 controls (mean age 57.2 years old; 73.1% men). Rhino‐orbital (±cerebral) mucormycosis (85.7%) was the most clinical presentation. Diabetes mellitus was more frequent in the cases than controls (75% vs. 42.3%; p =.015). Hypoxaemia during COVID‐19 illness was more common in controls than cases. The mean serum iron values (33 vs. 45 μg/dl, p =.03) and TIBC (166.6 vs. 201.6 μg/dl, p =.003) were significantly lower in CAM cases than controls. On multivariate analysis, we found a lower TIBC (odds ratio [OR] 0.97; 95% confidence interval [CI], 0.95–0.99) and diabetes mellitus (OR 5.23; 95% CI, 1.21–22.68) to be independently associated with CAM after adjusting for serum iron, ferritin and glucocorticoid therapy. The case fatality rate of CAM was 73.9%. The iron indices were not significantly different between CAM survivors and non‐survivors. Conclusions: The CAM is associated with lower TIBC levels than COVID‐19 subjects without mucormycosis, suggesting dysregulated iron metabolism in its pathogenesis. Further studies are required to confirm our preliminary observations. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 variants of concern (VOCs) have emerged worldwide, with implications on the spread of the pandemic. Characterizing the cross-reactivity of antibodies against these VOCs is necessary to understand the humoral response of non-hospitalized individuals previously infected with SARS-CoV-2, a population that remains understudied. Thirty-two SARS-CoV-2-positive (PCR-confirmed) and non-hospitalized Canadian adults were enrolled 14–21 days post-diagnosis in 2020, before the emergence of the B.1.351 (also known as Beta), B.1.617.2 (Delta) and P.1 (Gamma) VOCs. Sera were collected 4 and 16 weeks post-diagnosis. Antibody levels and pseudo-neutralization of the ectodomain of SARS-CoV-2 spike protein/human ACE-2 receptor interaction were analyzed with native, B.1.351, B.1.617.2 and P.1 variant spike proteins. Despite a lower response observed for the variant spike proteins, we report evidence of a sustained humoral response against native, B.1.351, B.1.617.2 and P.1 variant spike proteins among non-hospitalized Canadian adults. Furthermore, this response inhibited the interaction between the spike proteins from the different VOCs and ACE-2 receptor for ≥ 16 weeks post-diagnosis, except for individuals aged 18–49 years who showed no inhibition of the interaction between B.1.617.1 or B.1.617.2 spike and ACE-2. Interestingly, the affinity (KD) measured between the spike proteins (native, B.1.351, B.1.617.2 and P.1) and antibodies elicited in sera of infected and vaccinated (BNT162b2 and ChAdOx1 nCoV-19) individuals was invariant. Relative to sera from vaccine-naïve (and previously infected) individuals, sera from vaccinated individuals had higher antibody levels (as measured with label-free SPR) and more efficiently inhibited the spike–ACE-2 interactions, even among individuals aged 18–49 years, showing the effectiveness of vaccination. [ABSTRACT FROM AUTHOR]

Proprotein convertases subtilisin kexins are serine endoproteases, playing critical roles in the biological functions, including lipid, glucose, and bile acid metabolism, as well as cell proliferation, migration, and metastasis. Experimental studies have demonstrated the physiological functions of PCSKs and their association with diseases; however, studies on the evolutionary history and diversification of these proteins are missing. In the present research, a bioinformatics study was conducted on the molecular evolution of several PCSKs family members and gene loss events across placental mammalian. In order to detect evolutionary constraints and positive selection, the CodeML program of the PAML package was used. The results showed the positive selection to occur in PCSK1, PCSK3, PCSK5, and PCSK7. A decelerated rate of evolution was observed in PCSK7, PCSK3, and MBTPS1 in Carnivores compared to the rest of phylogeny, and an accelerated evolution of PCSK1, PCSK7, and MBTPS1 in Muridae family of rodents was found. Additionally, our results indicated pcsk9 gene loss in 12 species comprising Carnivores and bats (Chiroptera). Future studies are required to evaluate the functional relevance and selective evolutionary advantages associated with these modifications in PCSK proteins during evolution. [ABSTRACT FROM AUTHOR]

Patients with diabetes mellitus exhibit hyperglucagonemia, or excess glucagon secretion, which may be the underlying cause of the hyperglycemia of diabetes. Defective alpha cell secretory responses to glucose and paracrine effectors in both Type 1 and Type 2 diabetes may drive the development of hyperglucagonemia. Therefore, uncovering the mechanisms that regulate glucagon secretion from the pancreatic alpha cell is critical for developing improved treatments for diabetes. In this review, we focus on aspects of alpha cell biology for possible mechanisms for alpha cell dysfunction in diabetes: proglucagon processing, intrinsic and paracrine control of glucagon secretion, secretory granule dynamics, and alterations in intracellular trafficking. We explore possible clues gleaned from these studies in how inhibition of glucagon secretion can be targeted as a treatment for diabetes mellitus. [ABSTRACT FROM AUTHOR]

Superantigens are unconventional antigens which recognise immune receptors outside their usual recognition sites e.g. complementary determining regions (CDRs), to elicit a response within the target cell. T-cell superantigens crosslink T-cell receptors and MHC Class II molecules on antigen-presenting cells, leading to lymphocyte recruitment, induction of cytokine storms and T-cell anergy or apoptosis among many other effects. B-cell superantigens, on the other hand, bind immunoglobulins on B-cells, affecting opsonisation, IgG-mediated phagocytosis, and driving apoptosis. Here, through a review of the structural basis for recognition of immune receptors by superantigens, we show that their binding interfaces share specific physicochemical characteristics when compared with other protein-protein interaction complexes. Given that antibody-binding superantigens have been exploited extensively in industrial antibody purification, these observations could facilitate further protein engineering to optimize the use of superantigens in this and other areas of biotechnology. [ABSTRACT FROM AUTHOR]

Background: Despite marked advances in the clinical therapies, clinical outcome of most T-cell acute lymphoblastic leukemia (T-ALL) patients remains poor, due to the high risk of relapse, even after complete remission. Previous studies suggest that the NAD-dependent deacetylase sirtuin 1 (SIRT1) has a dual role in hematologic malignancies, acting as a tumor suppressor or tumor promoter depending on the tumor type. However, little is known about the expression and functions of SIRT1 in T-ALL leukemogenesis. Methods: Public RNA-seq data, a Notch1 driven T-ALL mouse model and γ-secretase inhibitor were used to identify SIRT1 expression in T-ALL. We knocked down SIRT1 expression with ShRNAs and assessed the impacts of SIRT1 deficiency on cell proliferation, colony formation, the cell cycle and apoptosis. Transgenic SIRT1 knockout mice were used to determine the function of SIRT1 in vivo. RT-PCR, western blot, co-immunoprecipitation and ubiquitination analyses were used to detect SIRT1, p27 and CDK2 expression and their interactions. Results: SIRT1 protein expression was positively correlated with the activation of Notch1. Downregulation of SIRT1 expression suppressed the proliferation and colony formation of T-ALL cell lines, which was reversed by SIRT1 overexpression. SIRT1 silencing prolonged the lifespan of T-ALL model mice. We demonstrated that p27 was involved in the downstream mechanism of cell cycle arrest induced by silencing SIRT1. SIRT1 increased the phosphorylation of p27 on Thr187 by deacetylating CDK2 and enhanced the interaction between p27 and SKP2 leading to the degradation of p27. Conclusion: Our findings suggest that SIRT1 is a promising target in T-ALL and offer a mechanistic link between the upregulation of SIRT1 and downregulation of p27. [ABSTRACT FROM AUTHOR]

Paramount efforts worldwide are seeking to increase understanding of the basic virology of SARS-CoV-2, characterize the spectrum of complications associated with COVID-19, and develop vaccines that can protect from new and recurrent infections with SARS-CoV-2. While we continue learning about this new virus, it is clear that 1) the virus is spread via the respiratory route, primarily by droplets and contact with contaminated surfaces and fomites, as well as by aerosol formation during invasive respiratory procedures; 2) the airborne route is still controversial; and 3) that those infected can spread the virus without necessarily developing COVID-19 (ie, asymptomatic). With the number of SARS-CoV-2 infections increasing globally, the possibility of co-infections and/or co-morbidities is becoming more concerning. Co-infection with Human Immunodeficiency Virus (HIV) is one such example of polyparasitism of interest. This military-themed comparative review of SARS-CoV-2 and HIV details their virology and describes them figuratively as separate enemy armies. HIV, an old enemy dug into trenches in individuals already infected, and SARS-CoV-2 the new army, attempting to attack and capture territories, tissues and organs, in order to provide resources for their expansion. This analogy serves to aid in discussion of three main areas of focus and draw attention to how these viruses may cooperate to gain the upper hand in securing a host. Here we compare their target, the key receptors found on those tissues, viral lifecycles and tactics for immune response surveillance. The last focus is on the immune response to infection, addressing similarities in cytokines released. While the majority of HIV cases can be successfully managed with antiretroviral therapy nowadays, treatments for SARS-CoV-2 are still undergoing research given the novelty of this army. [ABSTRACT FROM AUTHOR]

Studying the evolutionary diversification of mammalian antiviral defenses is of main importance to better understand our innate immune repertoire. The small HERC proteins are part of a multigene family, including HERC5 and HERC6, which have probably diversified through complex evolutionary history in mammals. Here, we performed mammalian-wide phylogenetic and genomic analyses of HERC5 and HERC6, using 83 orthologous sequences from bats, rodents, primates, artiodactyls, and carnivores—the top five representative groups of mammalian evolution. We found that HERC5 has been under weak and differential positive selection in mammals, with only primate HERC5 showing evidences of pathogen-driven selection. In contrast, HERC6 has been under strong and recurrent adaptive evolution in mammals, suggesting past and widespread genetic arms-races with viral pathogens. Importantly, the rapid evolution of mammalian HERC6 spacer domain suggests that it might be a host-pathogen interface, targeting viral proteins and/or being the target of virus antagonists. Finally, we identified a HERC5/6 chimeric gene that arose from independent duplication in rodent and bat lineages and encodes for a conserved HERC5 N-terminal domain and divergent HERC6 spacer and HECT domains. This duplicated chimeric gene highlights adaptations that potentially contribute to rodent and bat immunity. Our findings open new research avenues on the functions of HERC6 and HERC5/6 in mammals, and on their implication in antiviral innate immunity. [ABSTRACT FROM AUTHOR]

Purpose: In the present study, we investigated whether intra-islet GLP-1 production and its modulation have a role in apoptosis, proliferation or neogenesis that is compromised by protein restriction during the foetal and suckling periods. Methods: Exendin-4, a GLP-1 receptor agonist (treated groups), or saline (non-treated groups) was intraperitoneally administered for 15 days from 75 to 90 days of age in female adult rats consisting of offspring born to and suckled by mothers fed a control diet (control groups) and who had the same diet until 90 days of age or offspring born to and suckled by mothers fed a low-protein diet and who were fed the control diet after weaning until 90 days of age (protein-restricted group). Results: The β-cell mass was lower in the protein-restricted groups than in the control groups. Exendin-4 increased β-cell mass, regardless of the mother's protein intake. The colocalization of GLP-1/glucagon was higher in the protein-restricted rats than in control rats in both the exendin-4-treated and non-treated groups. The frequency of cleaved caspase-3-labelled cells was higher in the non-treated protein-restricted group than in the non-treated control group and was similar in the treated protein-restricted and treated control groups. Regardless of treatment with exendin-4, Ki67-labelled cell frequency and β-catenin/DAPI colocalization were elevated in the protein-restricted groups. Exendin-4 increased the area of endocrine cell clusters and β-catenin/DAPI and FoxO1/DAPI colocalization regardless of the mother's protein intake. Conclusions: Protein restriction in early life increased intra-islet GLP-1 production and β-cell proliferation, possibly mediated by the β-catenin pathway. [ABSTRACT FROM AUTHOR]

The loss of efferocytosis—the phagocytic clearance of apoptotic cells—is an initiating event in atherosclerotic plaque formation. While the loss of macrophage efferocytosis is a prerequisite for advanced plaque formation, the transcriptional and cellular events in the pre-lesion site that drive these defects are poorly defined. Transcriptomic analysis of macrophages recovered from early-stage human atherosclerotic lesions identified a 50-fold increase in the expression of GATA2, a transcription factor whose expression is normally restricted to the hematopoietic compartment. GATA2 overexpression in vitro recapitulated many of the functional defects reported in patient macrophages, including deficits at multiple stages in the efferocytic process. These findings included defects in the uptake of apoptotic cells, efferosome maturation, and in phagolysosome function. These efferocytic defects were a product of GATA2-driven alterations in the expression of key regulatory proteins, including Src-family kinases, Rab7 and components of both the vacuolar ATPase and NADPH oxidase complexes. In summary, these data identify a mechanism by which efferocytic capacity is lost in the early stages of plaque formation, thus setting the stage for the accumulation of uncleared apoptotic cells that comprise the bulk of atherosclerotic plaques. [ABSTRACT FROM AUTHOR]