•This paper investigates whether the economic policy uncertainty (EPU) index provided by Baker et al. (2016) can predict cryptocurrency volatility.•We show that the China EPU index can predict ...negatively the Bitcoin monthly volatility.•China's ban on crypto-trading does not result in a response in the volatility of Bitcoin.
We investigate the relationship between the economic policy uncertainty index (EPU) and cryptocurrency volatility. We find that a change in EPU of China predicts cryptocurrency volatility, but a change in the EPU of the U.S., Japan, or Korea has no such effect. Moreover, changes in the China EPU are negatively associated with Bitcoin and Litecoin future volatility, which may imply that Bitcoin and Litecoin are hedging tools against the EPU risk. However, changes in China EPU may not affect the cryptocurrency volatility after the Chinese government's regulation of crypto-trading.
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a poor inducer of innate antiviral immunity, and the underlying mechanism still needs further investigation. Here, we reported that ...SARS‐CoV‐2 NSP7 inhibited the production of type I and III interferons (IFNs) by targeting the RIG‐I/MDA5, Toll‐like receptor (TLR3)‐TRIF, and cGAS‐STING signaling pathways. SARS‐CoV‐2 NSP7 suppressed the expression of IFNs and IFN‐stimulated genes induced by poly (I:C) transfection and infection with Sendai virus or SARS‐CoV‐2 virus‐like particles. NSP7 impaired type I and III IFN production activated by components of the cytosolic dsRNA‐sensing pathway, including RIG‐I, MDA5, and MAVS, but not TBK1, IKKε, and IRF3‐5D, an active form of IRF3. In addition, NSP7 also suppressed TRIF‐ and STING‐induced IFN responses. Mechanistically, NSP7 associated with RIG‐I and MDA5 prevented the formation of the RIG‐I/MDA5−MAVS signalosome and interacted with TRIF and STING to inhibit TRIF‐TBK1 and STING‐TBK1 complex formation, thus reducing the subsequent IRF3 phosphorylation and nuclear translocation that are essential for IFN induction. In addition, ectopic expression of NSP7 impeded innate immune activation and facilitated virus replication. Taken together, SARS‐CoV‐2 NSP7 dampens type I and III IFN responses via disruption of the signal transduction of the RIG‐I/MDA5−MAVS, TLR3‐TRIF, and cGAS‐STING signaling pathways, thus providing novel insights into the interactions between SARS‐CoV‐2 and innate antiviral immunity.
Mismatch-repair deficiency testing plays a critical role in the identification of proband in Lynch Syndrome families and triaging patients with high stage or recurrent solid malignancies for check ...point inhibitor (Pembrolizumab) immunotherapy. We compared microsatellite shift patterns of microsatellite instability PCR analysis at 5 NCI recommended loci between microsatellite instability high endometrial carcinoma (n = 50) and microsatellite instability high colorectal cancer (n = 19). The endometrial cancer cohort included 45 endometrioid, 1 serous, and 4 clear cell carcinomas. Overall, 52% (26/50) of microsatellite instability high endometrial cancers showed minimal microsatellite shift (defined as a one to three nucleotide repeat shift at an involved locus) observed at least at one locus. Among microsatellite instability high endometrial cancers with minimal microsatellite shift, the frequencies at each involved locus were D2S123 (21/21, 100%), D17S250 (10/11, 89%), D5S346 (11/12, 92%), BAT25 (9/12, 80%), and BAT26 (8/21, 45%). Noticeably, 11 of the 26 cases (42%) showed only minimal shift. Among microsatellite instability high endometrial cancers with minimal microsatellite shift, 65% (17/26) had combined MLH1 and PMS2 loss, 8% (2/26) had combined MSH2 and MSH6 loss, 13% (3/26) had MSH6 loss and 15% (4/26) had loss of PMS2 by immunohistochemistry. In contrast, only 16% (3/19) had minimal microsatellite shift seen in colorectal cancer cohort with corresponding loss of MLH1/PMS2, MSH2/MSH6, or MSH6. Overall, 15% (7/50) of microsatellite instability high endometrial carcinomas showed isolated loss of MSH6 in contrast to 7% (1/15) seen in microsatellite instability high colorectal carcinomas. In conclusion, microsatellite instability high endometrial carcinomas have a significantly higher frequency of minimal microsatellite shift that coincides with a high percentage of combined loss of MLH1/PMS2. Microsatellite instability high endometrial cancers also have more frequent loss of MSH-6. Diagnostically, recognition of minimal microsatellite shift is crucial for accurate interpretation of microsatellite instability PCR data of endometrial carcinoma.
•Endo- and exogenous stimuli activate inflammasomes.•Inflammasome activation contributes to innate and adaptive immune responses.•Inflammasome activation induces IL-1β secretion.•IL-1β promotes Th17 ...cell differentiation via IL-1/IL-1R signaling.•Th17 responses are associated with inflammasome activation.
Immune sensing of exogenous molecules from microbes (e.g., pathogen-associated molecular patterns) and nonmicrobial molecules (e.g., asbestos, alum, and silica), as well as endogenous damage-associated molecular patterns (e.g., ATP, uric acid crystals, and amyloid A) activates innate immunity by inducing immune-related genes, including proinflammatory cytokines, which further facilitate the development of adaptive immunity. The roles of transcriptional responses downstream of immune sensing have been widely characterized in informing adaptive immunity; however, few studies focus on the effect of post-translational responses on the modulation of adaptive immune responses. Inflammasomes activated by the previously described endo- and exogenous stimuli autocatalytically induce intracellular pro-caspase-1, which cleaves the inactive precursors of interleukin-1β (IL-1β) and IL-18 into bioactive proinflammatory cytokines. IL-1β and IL-18 not only contribute to the host defense against infections by activating phagocytes, such as monocytes, macrophages, dendritic cells, and neutrophils, but also induce T-helper 17 (Th17)- and Th1-mediated adaptive immune responses. In synergy with IL-6 and IL-23, IL-1β activates IL-1 receptor (IL-1R) signaling to drive the differentiation of IL-17-producing Th17 cells, which not only play critical roles in host protective immunity to infections of bacteria, fungi, and certain viruses but also participate in the pathology of inflammatory disorders and tumorigenesis. Consequently, targeting inflammasomes and IL-1/IL-1R signaling may effectively improve the treatment of Th17-associated disorders, such as autoinflammatory diseases and cancers, thereby providing novel insights into drug development.
This paper examines the effect of political favoritism on economic inequality in the short run and political polarization in the long run. We exploit the sudden death of an authoritarian leader – ...President Chiang Ching-Kuo of Taiwan – in 1988 to generate plausibly exogenous variation in partiality. We find that Chiang’s nationalist regime conducted political favoritism broadly toward political immigrants via cronyism (allocating public sector positions) and also differentially toward specific subgroups of political immigrants via wage discrimination (offering higher wages to these subgroups within the public sector). Favoritism led to a 7.2 percent immigrant wage premium, which accounted for nearly three quarters of the immigrant–native wage gap at the time. This in turn propelled overall income inequality by 4.5 percent. Moreover, political favoritism breeds political polarization in the long run by pulling apart the political views of immigrants and natives. Compared with natives, immigrants who were exposed to favoritism tend to adopt political positions that are aligned with the nationalist party today: they are more likely to support unification with China, and are more inclined to trust the mainland Chinese government and its citizens. Exposed immigrant (native) swing voters are also more (less) likely to vote for the nationalist party today.
•We examine the effect of political favoritism on economic inequality in the short run and political polarization in the long run.•The death of an authoritarian leader in Taiwan offers plausibly exogenous variation in partiality.•The conduct of favoritism took on complementary forms: handing out public sector jobs and wage discrimination.•Favoritism led to an immigrant wage premium that amounted to three quarters of the immigrant-native wage gap.•It also breeds polarization in the long run by pulling apart their political views and voting.
The precise delivery of growth factors (GFs) in regenerative medicine is crucial for effective tissue regeneration and wound repair. However, challenges in achieving controlled release, such as ...limited half-life, potential overdosing risks, and delivery control complexities, currently hinder their clinical implementation. Despite the plethora of studies endeavoring to accomplish effective loading and gradual release of GFs through diverse delivery methods, the nuanced control of spatial and temporal delivery still needs to be elucidated. In response to this pressing clinical imperative, our review predominantly focuses on explaining the prevalent strategies employed for spatiotemporal delivery of GFs over the past five years. This review will systematically summarize critical aspects of spatiotemporal GFs delivery, including judicious bio-scaffold selection, innovative loading techniques, optimization of GFs activity retention, and stimulating responsive release mechanisms. It aims to identify the persisting challenges in spatiotemporal GFs delivery strategies and offer an insightful outlook on their future development. The ultimate objective is to provide an invaluable reference for advancing regenerative medicine and tissue engineering applications.
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•The spatiotemporal delivery of growth factors is pivotal in tissue regeneration engineering.•This review emphasized key factors for achieving spatiotemporal delivery of growth factors.•Various approaches for growth factor delivery in recent 5 years have been summarized in this review.
SARS‐CoV‐2 has developed a variety of approaches to counteract host innate antiviral immunity to facilitate its infection, replication and pathogenesis, but the molecular mechanisms that it employs ...are still not been fully understood. Here, we found that SARS‐CoV‐2 NSP8 inhibited the production of type I and III interferons (IFNs) by acting on RIG‐I/MDA5 and the signaling molecules TRIF and STING. Overexpression of NSP8 downregulated the expression of type I and III IFNs stimulated by poly (I:C) transfection and infection with SeV and SARS‐CoV‐2. In addition, NSP8 impaired IFN expression triggered by overexpression of the signaling molecules RIG‐I, MDA5, and MAVS, instead of TBK1 and IRF3‐5D, an active form of IRF3. From a mechanistic view, NSP8 interacts with RIG‐I and MDA5, and thereby prevents the assembly of the RIG‐I/MDA5‐MAVS signalosome, resulting in the impaired phosphorylation and nuclear translocation of IRF3. NSP8 also suppressed the TRIF‐ and STING‐ induced IFN expression by directly interacting with them. Moreover, ectopic expression of NSP8 promoted virus replications. Taken together, SARS‐CoV‐2 NSP8 suppresses type I and III IFN responses by disturbing the RIG‐I/MDA5−MAVS complex formation and targeting TRIF and STING signaling transduction. These results provide new insights into the pathogenesis of COVID‐19.
Kidney is a vital organ with high energy demands to actively maintain plasma hemodynamics, electrolytes and water homeostasis. Among the nephron segments, the renal tubular epithelium is endowed with ...high mitochondria density for their function in active transport. Acute kidney injury (AKI) is an important clinical syndrome and a global public health issue with high mortality rate and socioeconomic burden due to lack of effective therapy. AKI results in acute cell death and necrosis of renal tubule epithelial cells accompanied with leakage of tubular fluid and inflammation. The inflammatory immune response triggered by the tubular cell death, mitochondrial damage, associative oxidative stress, and the release of many tissue damage factors have been identified as key elements driving the pathophysiology of AKI. Autophagy, the cellular mechanism that removes damaged organelles via lysosome-mediated degradation, had been proposed to be renoprotective. An in-depth understanding of the intricate interplay between autophagy and innate immune response, and their roles in AKI pathology could lead to novel therapies in AKI. This review addresses the current pathophysiology of AKI in aspects of mitochondrial dysfunction, innate immunity, and molecular mechanisms of autophagy. Recent advances in renal tissue regeneration and potential therapeutic interventions are also discussed.
SARS-CoV-2 infections have resulted in a very large number of severe cases of COVID-19 and deaths worldwide. However, knowledge of SARS-CoV-2 infection, pathogenesis and therapy remains limited, ...emphasizing the urgent need for fundamental studies and drug development. Studies have shown that induction of macroautophagy/autophagy and hijacking of the autophagic machinery are essential for the infection and replication of SARS-CoV-2; however, the mechanism of this manipulation and the function of autophagy during SARS-CoV-2 infection remain unclear. In the present study, we identified ORF3a as an inducer of autophagy (in particular reticulophagy) and revealed that ORF3a localizes to the ER and induces RETREG1/FAM134B-related reticulophagy through the HMGB1-BECN1 (beclin 1) pathway. As a consequence, ORF3a induces ER stress and inflammatory responses through reticulophagy and then sensitizes cells to the acquisition of an ER stress-related early apoptotic phenotype and facilitates SARS-CoV-2 infection, suggesting that SARS-CoV-2 ORF3a hijacks reticulophagy and then disrupts ER homeostasis to induce ER stress and inflammatory responses during SARS-CoV-2 infection. These findings reveal the sequential induction of reticulophagy, ER stress and acute inflammatory responses during SARS-CoV-2 infection and imply the therapeutic potential of reticulophagy and ER stress-related drugs for COVID-19.
Abbreviations: CQ: chloroquine; DEGs: differentially expressed genes; ER: endoplasmic reticulum; GSEA: gene set enrichment analysis; HMGB1: high mobility group box 1; HMOX1: heme oxygenase 1; MERS-CoV: Middle East respiratory syndrome coronavirus; RETREG1/FAM134B: reticulophagy regulator 1; RTN4: reticulon 4; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TN: tunicamycin
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