Autophagy is a major degradation pathway that utilizes lysosome hydrolases to degrade cellular constituents and is often induced under cellular stress conditions to restore cell homeostasis. Another ...prime degradation pathway in the cells is ubiquitin-proteasome system (UPS), in which proteins tagged by certain types of polyubiquitin chains are selectively recognized and removed by proteasome. Although the two degradation pathways are operated independently with different sets of players, recent studies have revealed reciprocal cross talks between UPS and autophagy at multiple layers. In this review, we summarize the roles of protein ubiquitination and deubiquitination in controlling the initiation, execution, and termination of bulk autophagy as well as the role of ubiquitination in signaling certain types of selective autophagy. We also highlight how dysregulation of ubiquitin-mediated autophagy pathways is associated with a number of human diseases and the potential of targeting these pathways for disease intervention.
Many types of thermometers have been developed to measure body temperature. Infrared thermometers (IRT) are fast, convenient and ease to use. Two types of infrared thermometers are uses to measure ...body temperature: tympanic and forehead. With the spread of COVID-19 coronavirus, forehead temperature measurement is used widely to screen people for the illness. The performance of this type of device and the criteria for screening are worth studying. This study evaluated the performance of two types of tympanic infrared thermometers and an industrial infrared thermometer. The results showed that these infrared thermometers provide good precision. A fixed offset between tympanic and forehead temperature were found. The measurement values for wrist temperature show significant offsets with the tympanic temperature and cannot be used to screen fevers. The standard operating procedure (SOP) for the measurement of body temperature using an infrared thermometer was proposed. The suggestion threshold for the forehead temperature is 36 °C for screening of fever. The body temperature of a person who is possibly ill is then measured using a tympanic infrared thermometer for the purpose of a double check.
Particulate matter 2.5 (PM2.5) is a risk factor for lung cancer. In this study, we investigated the molecular mechanisms of PM2.5 exposure on lung cancer progression. We found that short‐term ...exposure to PM2.5 for 24 h activated the EGFR pathway in lung cancer cells (EGFR wild‐type and mutant), while long‐term exposure of lung cancer cells to PM2.5 for 90 days persistently promoted EGFR activation, cell proliferation, anchorage‐independent growth, and tumor growth in a xenograft mouse model in EGFR‐driven H1975 cancer cells. We showed that PM2.5 activated AhR to translocate into the nucleus and promoted EGFR activation. AhR further interacted with the promoter of TMPRSS2, thereby upregulating TMPRSS2 and IL18 expression to promote cancer progression. Depletion of TMPRSS2 in lung cancer cells suppressed anchorage‐independent growth and xenograft tumor growth in mice. The expression levels of TMPRSS2 were found to correlate with nuclear AhR expression and with cancer stage in lung cancer patient tissue. Long‐term exposure to PM2.5 could promote tumor progression in lung cancer through activation of EGFR and AhR to enhance the TMPRSS2‐IL18 pathway.
Synopsis
PM2.5 promotes lung cancer progression through activation of the AhR‐TMPRSS2‐IL18.
Exposure to PM2.5 activates EGFR pathway and promotes lung cancer progression.
Long‐term exposure to PM2.5 increases lung cancer cell proliferation, anchorage‐independent growth, and xenograft tumor growth in mice.
PM2.5 activates AhR to translocate into the nucleus and upregulates the expression of TMPRSS2.
Depletion of TMPRSS2 in lung cancer cells suppresses anchorage‐independent growth and xenograft tumor growth in mice.
TMPRSS2 upregulates IL I8 expression and promotes lung cancer progression.
PM2.5 promotes lung cancer progression through activation of the AhR‐TMPRSS2‐IL18.
Nitrogen accounts for approximately 60% of the fertilizer consumed each year; thus, it represents one of the major input costs for most nonlegume crops. Nitrate is one of the two major forms of ...nitrogen that plants acquire from the soil. Mechanistic insights into nitrate transport and signaling have enabled new strategies for enhancing nitrogen utilization efficiency, for lowering input costs for farming, and, more importantly, for alleviating environmental impacts (e.g., eutrophication and production of the greenhouse gas N
2
O). Over the past decade, significant progress has been made in understanding how nitrate is acquired from the surroundings, how it is efficiently distributed into different plant tissues in response to environmental changes, how nitrate signaling is perceived and transmitted, and how shoot and root nitrogen status is communicated. Several key components of these processes have proven to be novel tools for enhancing nitrate- and nitrogen-use efficiency. In this review, we focus on the roles of NRT1 and NRT2 in nitrate uptake and nitrate allocation among different tissues; we describe the functions of the transceptor NRT1.1, transcription factors, and small signaling peptides in nitrate signaling and tissue communication; and we compile the new strategies for improving nitrogen-use efficiency.
Autophagy, a cellular self-eating mechanism, is important for maintaining cell survival and tissue homeostasis in various stressed conditions. Although the molecular mechanism of autophagy induction ...has been well studied, how cells terminate autophagy process remains elusive. Here, we show that ULK1, a serine/threonine kinase critical for autophagy initiation, is a substrate of the Cul3-KLHL20 ubiquitin ligase. Upon autophagy induction, ULK1 autophosphorylation facilitates its recruitment to KLHL20 for ubiquitination and proteolysis. This autophagy-stimulated, KLHL20-dependent ULK1 degradation restrains the amplitude and duration of autophagy. Additionally, KLHL20 governs the degradation of ATG13, VPS34, Beclin-1, and ATG14 in prolonged starvation through a direct or indirect mechanism. Impairment of KLHL20-mediated regulation of autophagy dynamics potentiates starvation-induced cell death and aggravates diabetes-associated muscle atrophy. Our study identifies a key role of KLHL20 in autophagy termination by controlling autophagy-dependent turnover of ULK1 and VPS34 complex subunits and reveals the pathophysiological functions of this autophagy termination mechanism.
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•ULK1 autophosphorylation promotes its recruitment to KLHL20 for ubiquitination•KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1•KLHL20 mediates autophagy termination by degrading ULK1 and VPS34 complex subunits•Impairment of autophagy termination causes cell death and muscle atrophy
Liu et al. report a function of the Cul3-KLHL20 ubiquitin ligase in a feedback regulation, leading to autophagy termination through the degradation of multiple subunits of ULK1 and VPS34 complexes. This mechanism is important for cell survival and muscle homeostasis.
Summary
Background
Chronic hepatitis B virus (HBV) infection is a great health burden with geographical variations.
Aims
To explore genetic variants associated with chronic HBV infection.
Methods
The ...study included 15 352 participants seropositive for HBV core antibodies in Taiwan Biobank. Among them, 2591 (16.9%) seropositive for HBV surface antigen (HBsAg) were defined as having chronic HBV infection. All participants were examined for whole‐genome genotyping by Axiom‐Taiwan Biobank Array. The human leucocyte antigen (HLA) imputation was performed after identification of the variants within the region. Logistic regressions were used to estimate odds ratios (ORs) with 95% confidence intervals. Correlations of different HLA allele frequencies with HBsAg seroprevalence were evaluated across worldwide populations by Pearson correlation coefficients. Epitope prediction was performed for HLA alleles using NetMHCIIpan method.
Results
Located within a cluster of 450 single nucleotide polymorphisms in HLA class II, rs7770370 (P = 2.73 × 10−35) was significantly associated with HBV chronicity (Pcorrected < 8.6 × 10−8). Imputation analyses showed that HLA‐DPA1*02:02 and HLA‐DPB1*05:01 were associated with chronic HBV, with adjusted ORs of 1.43 (1.09‐1.89) and 1.61 (1.29‐2.01). These allele frequencies were positively correlated with global HBsAg seroprevalence, with R of 0.75 and 0.62 respectively (P < 0.05). HLA‐DRB1*13:02, HLA‐DQA1* 01:02 and HLA‐DQB1*06:09 associated with HBV chronicity negatively, with adjusted ORs of 0.31 (0.17‐0.58), 0.70 (0.56‐0.87) and 0.33 (0.18‐0.63). These HLA alleles had various binding affinities to the predicted epitopes derived from HBV nucleocapsid protein.
Conclusions
HLA class II variants are relevant for chronicity after HBV acquisition.
We conducted a genome‐wide association study to discover genetic variants associated with hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC). We genotyped 502 HCC cases and 749 non‐HCC ...controls using the Axiom‐CHB genome‐wide array. After identifying single‐nucleotide polymorphism clusters located in the human leukocyte antigen (HLA) region which were potentially associated with HCC, HLA‐DQB1 genotyping was performed to analyze 994 anti‐HCV seropositives collected in the period 1991‐2013 in a community‐based cohort for evaluating long‐term predictability of HLA variants for identifying the risk of HCC. Cox proportional hazards models were used to estimate the hazard ratios and 95% confidence intervals of HLA genotypes for determining the aforementioned HCC risk. Eight single‐nucleotide polymorphisms in the proximity of HLA‐DQB1 were associated with HCC (P < 8.7 × 10−8) in the genome‐wide association study. Long‐term follow‐up showed a significant association with HLA‐DQB1*03:01 and DQB1*06:02 (P < 0.05). The adjusted hazard ratios associated with HCC were 0.45 (0.30‐0.68) and 2.11 (1.34‐3.34) for DQB1*03:01 and DQB1*06:02, respectively. After stratification by HCV genotypes, DQB1*03:01 showed protective effects only in patients with HCV genotype 1, whereas DQB1*06:02 conferred risk of HCC only in patients with HCV non‐1 genotypes. HLA imputation analyses revealed that HLA‐DRB1*15:01, which is in linkage disequilibrium with DQB1*06:02, also increased the risk of HCC (odds ratio, 1.96; 95% confidence interval, 1.31‐2.93). Haplotype analysis supported that DQB1*03:01 and DQB1*06:02 are primarily protective and susceptible variants, respectively. Conclusion: HLA‐DQB1 was independently associated with HCC; HCV genotypes modified the effects of HLA‐DQB1 on the risk of HCC. (Hepatology 2018;67:651‐661).
TP53 alterations are frequent relapse‐acquired mutations in childhood acute lymphoblastic leukemia (ALL). The present study evaluated the clinical significance of relapsed childhood ALL in Taiwan. ...Diagnostic and/or relapsed bone marrow or peripheral blood was obtained from 111 children with relapsed ALL who were initially treated by using Taiwan Pediatric Oncology Group (TPOG) ALL protocols from January 1997 to May 2018. Mutations were detected by PCR and sequencing, as well as by multiplex ligation‐dependent probe amplification to detect copy number alterations. Copy number and/or sequence alterations of TP53 were detected in 29% (28 of 98) and in 46% (6 of 13) of patients with relapsed B‐cell and T‐cell ALL, respectively. This incidence was much higher than that in several similar studies conducted in Caucasian populations. Seventy percent of all TP53 alterations were gained at relapse in 67 matched samples by back‐tracking matched diagnostic samples. TP53 alterations were associated with lower 5‐year event‐free survival (EFS) and overall survival (OS) rates (P = .013 and P = .0002, respectively). Multivariate analysis confirmed the prognostic significance of TP53 alterations. Forty‐five patients received hematopoietic stem‐cell transplantations post‐relapse. Patients with TP53 alterations (14/45) had inferior 5‐year EFS and OS than patients without TP53 alterations after transplantation (P = .002 and P = .001, respectively). The significance of these TP53 alterations for patients who received transplantations was confirmed by multivariate analysis. In conclusion, TP53 alterations were enriched and useful as prognostic markers in relapsed childhood ALL.
Relapsed pediatric ALL patients with TP53 alterations had inferior 5‐year EFS and OS. TP53 alterations were enriched and useful as prognostic markers in relapsed childhood ALL.
To explore whether a cross-talk exists between PARP inhibition and PD-L1/PD-1 immune checkpoint axis, and determine whether blockade of PD-L1/PD-1 potentiates PARP inhibitor (PARPi) in tumor ...suppression.
Breast cancer cell lines, xenograft tumors, and syngeneic tumors treated with PARPi were assessed for PD-L1 expression by immunoblotting, IHC, and FACS analyses. The phospho-kinase antibody array screen was used to explore the underlying mechanism of PARPi-induced PD-L1 upregulation. The therapeutic efficacy of PARPi alone, PD-L1 blockade alone, or their combination was tested in a syngeneic tumor model. The tumor-infiltrating lymphocytes and tumor cells isolated from syngeneic tumors were analyzed by CyTOF and FACS to evaluate the activity of antitumor immunity in the tumor microenvironment.
PARPi upregulated PD-L1 expression in breast cancer cell lines and animal models. Mechanistically, PARPi inactivated GSK3β, which in turn enhanced PARPi-mediated PD-L1 upregulation. PARPi attenuated anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 resensitized PARPi-treated cancer cells to T-cell killing. The combination of PARPi and anti-PD-L1 therapy compared with each agent alone significantly increased the therapeutic efficacy
Our study demonstrates a cross-talk between PARPi and tumor-associated immunosuppression and provides evidence to support the combination of PARPi and PD-L1 or PD-1 immune checkpoint blockade as a potential therapeutic approach to treat breast cancer.
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Due to its specificity, fluorescence microscopy has become a quintessential imaging tool in cell biology. However, photobleaching, phototoxicity, and related artifacts continue to limit fluorescence ...microscopy's utility. Recently, it has been shown that artificial intelligence (AI) can transform one form of contrast into another. We present phase imaging with computational specificity (PICS), a combination of quantitative phase imaging and AI, which provides information about unlabeled live cells with high specificity. Our imaging system allows for automatic training, while inference is built into the acquisition software and runs in real-time. Applying the computed fluorescence maps back to the quantitative phase imaging (QPI) data, we measured the growth of both nuclei and cytoplasm independently, over many days, without loss of viability. Using a QPI method that suppresses multiple scattering, we measured the dry mass content of individual cell nuclei within spheroids. In its current implementation, PICS offers a versatile quantitative technique for continuous simultaneous monitoring of individual cellular components in biological applications where long-term label-free imaging is desirable.
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