With global expansion of the COVID-19 pandemic and the emergence of new variants, extensive efforts have been made to develop highly effective antiviral drugs and vaccines against SARS-CoV-2. The ...interactions of coronaviruses with host antiviral interferon pathways ultimately determine successful viral replication and SARS-CoV-2-induced pathogenesis. Innate immune receptors play an essential role in host defense against SARS-CoV-2 via the induction of IFN production and signaling. Here, we summarize the recent advances in innate immune sensing mechanisms of SARS-CoV-2 and various strategies by which SARS-CoV-2 antagonizes antiviral innate immune signaling pathways, with a particular focus on mechanisms utilized by multiple SARS-CoV-2 proteins to evade interferon induction and signaling in host cell. Understanding the underlying immune evasion mechanisms of SARS-CoV-2 is essential for the improvement of vaccines and therapeutic strategies.
In contrast to the bulk of the tumor, a subset of cancer cells called cancer stem cells (CSC; or tumor‐initiating cells) is characterized by self‐renewal, unlimited proliferative potential, ...expression of multidrug resistance proteins, active DNA repair capacity, apoptosis resistance, and a considerable developmental plasticity. Due to these properties, CSCs display increased resistance to chemo‐ and radiotherapy. Recent findings indicate that aberrant functions of proteoglycans (PGs) and glycosaminoglycans (GAGs) contribute substantially to the CSC phenotype and therapeutic resistance. In this review, we summarize how the diverse functions of the glycoproteins and carbohydrates facilitate acquisition and maintenance of the CSC phenotype, and how this knowledge can be exploited to develop novel anticancer therapies. For example, the large transmembrane chondroitin sulfate PG NG2/CSPG4 marks stem cell (SC) populations in brain tumors. Cell surface heparan sulfate PGs of the syndecan and glypican families modulate the stemness‐associated Wnt, hedgehog, and notch signaling pathways, whereas the interplay of hyaluronan in the SC niche with CSC CD44 determines the maintenance of stemness and promotes therapeutic resistance. A better understanding of the molecular mechanisms by which PGs and GAGs regulate CSC function will aid the development of targeted therapeutic approaches which could avoid relapse after an otherwise successful conventional therapy. Chimeric antigen receptor T cells, PG‐primed dendritic cells, PG‐targeted antibody–drug conjugates, and inhibitory peptides and glycans have already shown highly promising results in preclinical models.
The aberrant expression of proteoglycans (PGs) and glycosaminoglycans (GAGs) in cancer cells and the tumor microenvironment makes an important contribution to tumor progression by modulation of the cancer stem cell (CSC) phenotype and the development of resistance against therapeutic strategies. PGs and GAGs modulate cellular signaling pathways that favor self‐renewal, establishment, and maintenance of CSCs in different niches, with key roles in tumor cell survival, drug resistance, and metastasis.
Channel-Mediated Tonic GABA Release from Glia Lee, Soojung; Yoon, Bo-Eun; Berglund, Ken ...
Science (American Association for the Advancement of Science),
11/2010, Letnik:
330, Številka:
6005
Journal Article
Recenzirano
Odprti dostop
Synaptic inhibition is based on both tonic and phasic release of the inhibitory transmitter γ-aminobutyric acid (GABA). Although phasic GABA release arises from Ca²⁺-dependent exocytosis from ...neurons, the mechanism of tonic GABA release is unclear. Here we report that tonic inhibition in the cerebellum is due to GABA being released from glial cells by permeation through the Bestrophin 1 (Best1) anion channel. We demonstrate that GABA directly permeates through Best1 to yield GABA release and that tonic inhibition is eliminated by silencing of Best1. Glial cells express both GABA and Best1, and selective expression of Best1 in glial cells, after preventing general expression of Best1, fully rescues tonic inhibition. Our results identify a molecular mechanism for tonic inhibition and establish a role for interactions between glia and neurons in mediating tonic inhibition.
Key points
Here we show that glial gamma aminobutyric acid (GABA) is produced by monoamine oxidase B (MAOB), utilizing a polyamine, putrescine.
The concentration of GABA in Bergmann glial cells is ...estimated to be around 5–10 mM.
General gene silencing of MAOB resulted in elimination of tonic GABA currents recorded from granule cells in the cerebellum and medium spiny neurons (MSN) in the striatum.
Glial‐specific rescue of MAOB resulted in complete restoration of tonic GABA currents.
Our results identify MAOB as a synthesizing enzyme of glial GABA, which is released to mediate tonic inhibition in the cerebellum and striatum.
GABA is the major inhibitory transmitter in the brain and is released not only from a subset of neurons but also from glia. Although neuronal GABA is well known to be synthesized by glutamic acid decarboxylase (GAD), the source of glial GABA is unknown. After estimating the concentration of GABA in Bergmann glia to be around 5–10 mm by immunogold electron microscopy, we demonstrate that GABA production in glia requires MAOB, a key enzyme in the putrescine degradation pathway. In cultured cerebellar glia, both Ca2+‐induced and tonic GABA release are significantly reduced by both gene silencing of MAOB and the MAOB inhibitor selegiline. In the cerebellum and striatum of adult mice, general gene silencing, knock out of MAOB or selegiline treatment resulted in elimination of tonic GABA currents recorded from granule neurons and medium spiny neurons. Glial‐specific rescue of MAOB resulted in complete rescue of tonic GABA currents. Our results identify MAOB as a key synthesizing enzyme of glial GABA, which is released via bestrophin 1 (Best1) channel to mediate tonic inhibition in the brain.
Immunosenescence is characterized by a progressive deterioration of the immune system associated with aging. Multiple components of both innate and adaptive immune systems experience aging-related ...changes, such as alterations in the number of circulating monocytic and dendritic cells, reduced phagocytic activities of neutrophils, limited diversity in B/T cell repertoire, T cell exhaustion or inflation, and chronic production of inflammatory cytokines known as inflammaging. The elderly are less likely to benefit from vaccinations as preventative measures against infectious diseases due to the inability of the immune system to mount a successful defense. Therefore, aging is thought to decrease the efficacy and effectiveness of vaccines, suggesting aging-associated decline in the immunogenicity induced by vaccination. In this review, we discuss aging-associated changes in the innate and adaptive immunity and the impact of immunosenescence on viral infection and immunity. We further explore recent advances in strategies to enhance the immunogenicity of vaccines in the elderly. Better understanding of the molecular mechanisms underlying immunosenescence-related immune dysfunction will provide a crucial insight into the development of effective elderly-targeted vaccines and immunotherapies.
This paper investigates a parabolic–elliptic chemotaxis-consumption system with signal dependent sensitivity χ=χ(c) under no-flux/Dirichlet boundary conditions. For general χ which may allow ...singularities at c=0, the global existence and boundedness of radial large data solutions are established in dimensions d≥2. In particular, when χ(c)=1, we also find that the constructed solution converges asymptotically to a nonhomogeneous steady state if the initial mass is small. On the other hand, for the system with χ(c)=c, a Lyapunov-type inequality is derived. This inequality not only leads to a result on global existence of smooth solutions with non-radial large data in two dimensions but moreover, provides long-time asymptotics of non-radial (d=2) and radial (d≥2) solutions at suitably small mass levels.
Non-alcoholic fatty liver disease (NAFLD) is currently one of the most common types of chronic liver injury. Elevated serum uric acid is a strong predictor of the development of fatty liver as well ...as metabolic syndrome. Here we demonstrate that uric acid induces triglyceride accumulation by SREBP-1c activation via induction of endoplasmic reticulum (ER) stress in hepatocytes. Uric acid-induced ER stress resulted in an increase of glucose-regulated protein (GRP78/94), splicing of the X-box-binding protein-1 (XBP-1), the phosphorylation of protein kinase RNA-like ER kinase (PERK), and eukaryotic translation initiation factor-2α (eIF-2α) in cultured hepatocytes. Uric acid promoted hepatic lipogenesis through overexpression of the lipogenic enzyme, acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1) via activation of SREBP-1c, which was blocked by probenecid, an organic anion transport blocker in HepG2 cells and primary hepatocytes. A blocker of ER stress, tauroursodeoxycholic acid (TUDCA), and an inhibitor of SREBP-1c, metformin, blocked hepatic fat accumulation, suggesting that uric acid promoted fat synthesis in hepatocytes via ER stress-induced activation of SREBP-1c. Uric acid-induced activation of NADPH oxidase preceded ER stress, which further induced mitochondrial ROS production in hepatocytes. These studies provide new insights into the mechanisms by which uric acid stimulates fat accumulation in the liver.
Background and purpose - We aimed to evaluate the ability of artificial intelligence (a deep learning algorithm) to detect and classify proximal humerus fractures using plain anteroposterior shoulder ...radiographs.
Patients and methods - 1,891 images (1 image per person) of normal shoulders (n = 515) and 4 proximal humerus fracture types (greater tuberosity, 346; surgical neck, 514; 3-part, 269; 4-part, 247) classified by 3 specialists were evaluated. We trained a deep convolutional neural network (CNN) after augmentation of a training dataset. The ability of the CNN, as measured by top-1 accuracy, area under receiver operating characteristics curve (AUC), sensitivity/specificity, and Youden index, in comparison with humans (28 general physicians, 11 general orthopedists, and 19 orthopedists specialized in the shoulder) to detect and classify proximal humerus fractures was evaluated.
Results - The CNN showed a high performance of 96% top-1 accuracy, 1.00 AUC, 0.99/0.97 sensitivity/specificity, and 0.97 Youden index for distinguishing normal shoulders from proximal humerus fractures. In addition, the CNN showed promising results with 65-86% top-1 accuracy, 0.90-0.98 AUC, 0.88/0.83-0.97/0.94 sensitivity/specificity, and 0.71-0.90 Youden index for classifying fracture type. When compared with the human groups, the CNN showed superior performance to that of general physicians and orthopedists, similar performance to orthopedists specialized in the shoulder, and the superior performance of the CNN was more marked in complex 3- and 4-part fractures.
Interpretation - The use of artificial intelligence can accurately detect and classify proximal humerus fractures on plain shoulder AP radiographs. Further studies are necessary to determine the feasibility of applying artificial intelligence in the clinic and whether its use could improve care and outcomes compared with current orthopedic assessments.
Exposure to ultraviolet (UV) radiation is a major contributing factor to premature aging (photoaging) and skin cancer. In vitro models of cellular senescence have proven to be very useful for the ...study of slow and progressive accumulation of damage resulting in the growth arrest of aging skin cells. In this study, we compared UVA-induced cellular responses in non-senescent (NS) vs. senescent (S) human dermal fibroblasts (HDFs). HDFs were irradiated with a single dose of UVA (7.5 J/cm2) and QuantSeq 3' mRNA sequencing was performed to assess differential gene expression. Both NS and S HDFs expressed similar numbers of differentially expressed genes, although distinct sets of genes were differentially expressed between the two groups. Higher expression of matrix metalloproteinases (MMPs) and Toll-like receptor (TLR) pathway genes, such as TLR4, MyD88, and CXCL-8, was detected in S HDFs as compared with NS HDFs, and UVA exposure led to a downregulation of collagen genes, such as COL8A2 and COL5A3. Consistent with gene expression profiling, enhanced IL-6 and IL-8 secretion was observed in S HDFs compared with NS HDFs, in response to UVA. Furthermore, we show that TLR4-mediated ERK pathway is responsible for the UVA-mediated mitochondrial dysfunction as well as increased secretion of MMP-1 and IL-8 in S HDFs. Taken together, our results demonstrate the UVA-induced common and distinct molecular patterns of cellular responses between NS and S HDFs and suggest TLR4/ERK pathways as candidate targets to reduce senescent phenotypes.
Small Departures, Big Continuities? Tandoc, Edson C.; Oh, Soo-Kwang
Journalism studies (London, England),
08/2017, Letnik:
18, Številka:
8
Journal Article
Recenzirano
Through a content analysis of big data journalism stories from The Guardian (N = 260), a pioneer in contemporary big data journalism, we sought to investigate how the practice of big data journalism ...compares with traditional news values, norms, and routines. Findings suggested that big data journalism shows new trends in terms of how sources are used, but still generally adhere to traditional news values and formats such as objectivity and use of visuals.
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