Interferon-stimulated gene PVRL4 broadly suppresses viral entry by inhibiting viral-cellular membrane fusion.

BACKGROUND: Viral infection elicits the type I interferon (IFN-I) response in host cells and subsequently inhibits viral infection through inducing hundreds of IFN-stimulated genes (ISGs) that counteract many steps in the virus life cycle. However, most of ISGs have unclear functions and mechanisms in viral infection. Thus, more work is required to elucidate the role and mechanisms of individual ISGs against different types of viruses. RESULTS: Herein, we demonstrate that poliovirus receptor-like protein4 (PVRL4) is an ISG strongly induced by IFN-I stimulation and various viral infections. Overexpression of PVRL4 protein broadly restricts growth of enveloped RNA and DNA viruses, including vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) whereas deletion of PVRL4 in host cells increases viral infections. Mechanistically, it suppresses viral entry by blocking viral-cellular membrane fusion through inhibiting endosomal acidification. The vivo studies demonstrate that Pvrl4-deficient mice were more susceptible to the infection of VSV and IAV. CONCLUSION: Overall, our studies not only identify PVRL4 as an intrinsic broad-spectrum antiviral ISG, but also provide a candidate host-directed target for antiviral therapy against various viruses including SARS-CoV-2 and its variants in the future.

The aldehyde dehydrogenase ALDH1B1 exerts antiviral effects through the aggregation of the adaptor MAVS.

Type I interferons (IFNs) are produced by almost all cell types and play a vital role in host defense against viral infection. Infection with an RNA virus activates receptors such as RIG-I, resulting in the recruitment of the adaptor protein MAVS to the RIG-I-like receptor (RLR) signalosome and the formation of prion-like functional aggregates of MAVS, which leads to IFN-ß production. Here, we identified the aldehyde dehydrogenase 1B1 (ALDH1B1) as a previously uncharacterized IFN-stimulated gene (ISG) product with critical roles in the antiviral response. Knockout of ALDH1B1 increased, whereas overexpression of ALDH1B1 restricted, the replication of RNA viruses, such as vesicular stomatitis virus (VSV), Zika virus (ZIKV), dengue virus (DENV), and influenza A virus (IAV). We found that ALDH1B1 localized to mitochondria, where it interacted with the transmembrane domain of MAVS to promote MAVS aggregation. ALDH1B1 was recruited to MAVS aggregates. In addition, ALDH1B1 also enhanced the interaction between activated RIG-I and MAVS, thus increasing IFN-ß production and the antiviral response. Furthermore, Aldh1b1-/- mice developed more severe symptoms than did wild-type mice upon IAV infection. Together, these data identify an aldehyde dehydrogenase in mitochondria that functionally regulates MAVS-mediated signaling and the antiviral response.

Ensuring access to justice: the need for community paralegals to end AIDS by 2030.

INTRODUCTION: The HIV response has long recognized that certain "key populations" such as individuals in detention, adolescent girls and young women, sex workers, people who use drugs, LGBTQ individuals, migrants and others face higher barriers to access to, uptake of, and retention in HIV prevention and treatment services. One approach to addressing these barriers is the training of community paralegals to advocate for the rights of individuals and to address discrimination in health settings. DISCUSSION: Community paralegal programmes have been able to successfully address rights violations that impact access to health services and underlying determinants of health across a range of countries and populations, focusing upon issues such as discrimination and the denial of health services; unlawful detention of outreach workers, sex workers, persons who use drugs and men who have sex with men; and harmful traditional practices and gender-based violence. In addition to resolving specific cases, evaluations of paralegal programmes have found that these programmes increased legal literacy among key populations at risk of HIV and increased understanding of human rights among healthcare providers, resulting in improved access to HIV services. Some evaluations have noted challenges related to the sustainability of paralegal programmes similar to those raised with community health worker programmes more broadly. CONCLUSIONS: To achieve global HIV goals, funding for legal literacy and paralegal programmes should be increased and interventions should be rigorously evaluated. Efforts should target discrimination in access to HIV prevention and treatment and criminalization of key populations, two key barriers to ensuring access to HIV prevention and treatment services.

Regulation of DNA damage response by trimeric G-proteins.

Upon sensing DNA double-strand breaks (DSBs), eukaryotic cells either die or repair DSBs via one of the two competing pathways, i.e., non-homologous end-joining (NHEJ) or homologous recombination (HR). We show that cell fate after DSBs hinges on GIV/Girdin, a guanine nucleotide-exchange modulator of heterotrimeric Giα•ßγ protein. GIV suppresses HR by binding and sequestering BRCA1, a key coordinator of multiple steps within the HR pathway, away from DSBs; it does so using a C-terminal motif that binds BRCA1's BRCT-modules via both phospho-dependent and -independent mechanisms. Using another non-overlapping C-terminal motif GIV binds and activates Gi and enhances the "free" Gßγ→PI-3-kinase→Akt pathway, which promotes survival and is known to suppress HR, favor NHEJ. Absence of GIV, or loss of either of its C-terminal motifs enhanced cell death upon genotoxic stress. Because GIV selectively binds other BRCT-containing proteins suggests that G-proteins may fine-tune sensing, repair, and survival after diverse types of DNA damage.

SERTAD3 induces proteasomal degradation of ZIKV capsid protein and represents a therapeutic target.

Zika virus (ZIKV) is a mosquito-borne RNA virus that belongs to the Flaviviridae family. While flavivirus replication is known to occur in the cytoplasm, a significant portion of the viral capsid protein localizes to the nucleus during infection. However, the role of the nuclear capsid is less clear. Herein, we demonstrated SERTA domain containing 3 (SERTAD3) as an antiviral interferon stimulatory gene product had an antiviral ability to ZIKV but not JEV. Mechanistically, we found that SERTAD3 interacted with the capsid protein of ZIKV in the nucleolus and reduced capsid protein abundance through proteasomal degradation. Furthermore, an eight amino acid peptide of SERTAD3 was identified as the minimum motif that binds with ZIKV capsid protein. Remarkably, the eight amino acids synthetic peptide from SERTAD3 significantly prevented ZIKV infection in culture and pregnant mouse models. Taken together, these findings not only reveal the function of SERTAD3 in promoting proteasomal degradation of a specific viral protein but also provide a promising host-targeted therapeutic strategy against ZIKV infection.

Expression and significance of CDX2, FXR, and TGR5 in esophageal cancer.

This study explored the expression and significance of three critical morphogenesis genes in normal esophagus, reflux esophagitis (RE), Barrett's esophagus (BE), esophageal adenocarcinoma (EA), and esophageal squamous cell carcinoma (ESCC). Esophageal tissue samples and tissue microarrays were used. CDX2, FXR, and TGR5 protein expression were measured by immunohistochemistry in normal esophageal, RE, BE, EA, and ESCC tissues. All 3 proteins had markedly changed expression during the progression of EA. The expressions of CDX2 and FXR were positively correlated in EA. In addition, TGR5 expression was positively correlated with CDX2 in RE and BE. The expressions of CDX2 and FXR were also positively correlated in ESCC. Although CDX2, FXR, and TGR5 were upregulated in ESCC, these factors might not be markers for the prognosis of ESCC. These results suggested that CDX2, FXR, and TGR5 might play different roles in EA and ESCC. They may represent novel therapeutic targets for patients with these cancers.

Genetic basis analysis of key Loci in 23 Yannong series wheat cultivars/lines.

Fungal diseases, drought, pre-harvest sprouting (PHS) and other biotic and abiotic stresses have seriously affected the quality and yield in wheat production. Identifying related genes/loci in released cultivars/lines can provide reference information and theoretical basis for wheat improvement. Yannong series wheat cultivars/lines have distinctive characteristics in wheat cultivars and play an important role in genetic improvement and production of Chinese wheat production system. To dissect their genetic basis of the stress-resistant traits, in this study, 23 representative Yannong series wheat cultivars/lines were tested by 58 molecular markers for 40 genes related to adaptability, disease resistance and stress tolerance to clarify the genetic composition of the key loci. The results showed that most of the tested wheat accessions carried dwarfing genes RhtB1b/RhtD1b/Rht8 and recessive vernalization genes vrn-A1/vrn-B1/vrn-D1/vrn-B3. It was also consistent with the phenotypic traits of tested Yannong series wheat which were dwarf and winter or semi winter wheat. In addition, the overall level of seedling powdery mildew resistance in 23 Yannong wheat cultivars/lines was moderate or inadequate. Eleven accessions carried none of the tested Pm genes and twelve accessions carried Pm2, Pm6, Pm42 and Pm52 singly or in combination. Then, 23 wheat cultivars/lines were also tested by 17 diagnostic markers for 14 Yr genes. The results showed that 16 wheat cultivars/lines were likely to carry one or more of tested Yr genes, whereas Yannong 15, Yannong 17, Yannong 23, Yannong 24, Yannong 377, Yannong 572 and Yannong 999 carried none of the tested Yr genes. Moreover, in our study, nine markers for four genes related to drought tolerance and PHS were used to evaluate the stress tolerance of the 23 wheat cultivars/lines. The results indicated that all 23 wheat cultivars/lines carried drought resistance genes Ta-Dreb1/TaCRT-D, indicating that they had the drought resistance to the extent. Except for Yannong 30, Yannong 377, Yannong 390, Yannong 745 and Yannong 1766, other wheat cultivars/lines carried one to three elite PHS-resistant alleles Vp-1Bc/Vp-1Bf/TaAFP-1Bb.

Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome.

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses and spreads by metastasis to the liver1. Cancer-associated fibroblasts, the extracellular matrix and type I collagen (Col I) support2,3 or restrain the progression of PDAC and may impede blood supply and nutrient availability4. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers to escape nutrient limitation, remain poorly understood. Here we show that matrix-metalloprotease-cleaved Col I (cCol I) and intact Col I (iCol I) exert opposing effects on PDAC bioenergetics, macropinocytosis, tumour growth and metastasis. Whereas cCol I activates discoidin domain receptor 1 (DDR1)-NF-κB-p62-NRF2 signalling to promote the growth of PDAC, iCol I triggers the degradation of DDR1 and restrains the growth of PDAC. Patients whose tumours are enriched for iCol I and express low levels of DDR1 and NRF2 have improved median survival compared to those whose tumours have high levels of cCol I, DDR1 and NRF2. Inhibition of the DDR1-stimulated expression of NF-κB or mitochondrial biogenesis blocks tumorigenesis in wild-type mice, but not in mice that express MMP-resistant Col I. The diverse effects of the tumour stroma on the growth and metastasis of PDAC and on the survival of patients are mediated through the Col I-DDR1-NF-κB-NRF2 mitochondrial biogenesis pathway, and targeting components of this pathway could provide therapeutic opportunities.

Identification of the powdery mildew resistance gene in wheat breeding line Yannong 99102-06188 via bulked segregant exome capture sequencing.

Powdery mildew of wheat (Triticum aestivum), caused by Blumeria graminis f.sp. tritici (Bgt), is a destructive disease that seriously threatens the yield and quality of its host. Identifying resistance genes is the most attractive and effective strategy for developing disease-resistant cultivars and controlling this disease. In this study, a wheat breeding line Yannong 99102-06188 (YN99102), an elite derivative line from the same breeding process as the famous wheat cultivar Yannong 999, showed high resistance to powdery mildew at the whole growth stages. Genetic analysis was carried out using Bgt isolate E09 and a population of YN99102 crossed with a susceptible parent Jinhe 13-205 (JH13-205). The result indicated that a single recessive gene, tentatively designated pmYN99102, conferred seedling resistance to the Bgt isolate E09. Using bulked segregant exome capture sequencing (BSE-Seq), pmYN99102 was physically located to a ~33.7 Mb (691.0-724.7 Mb) interval on the chromosome arm 2BL, and this interval was further locked in a 1.5 cM genetic interval using molecular markers, which was aligned to a 9.0 Mb physical interval (699.2-708.2 Mb). Based on the analysis of physical location, origin, resistant spectrum, and inherited pattern, pmYN99102 differed from those of the reported powdery mildew (Pm) resistance genes on 2BL, suggesting pmYN99102 is most likely a new Pm gene/allele in the targeted interval. To transfer pmYN99102 to different genetic backgrounds using marker-assisted selection (MAS), 18 closely linked markers were tested for their availability in different genetic backgrounds for MAS, and all markers expect for YTU103-97 can be used in MAS for tracking pmYN99102 when it transferred into those susceptible cultivars.

TRIM22 suppresses Zika virus replication by targeting NS1 and NS3 for proteasomal degradation.

BACKGROUND: Recognition of viral invasion by innate antiviral immune system triggers activation of the type I interferon (IFN-I) and proinflammatory signaling pathways. Subsequently, IFN-I induction regulates expression of a group of genes known as IFN-I-stimulated genes (ISGs) to block viral infection. The tripartite motif containing 22 (TRIM22) is an ISG with strong antiviral functions. RESULTS: Here we have shown that the TRIM22 has been strongly upregulated both transcriptionally and translationally upon Zika virus (ZIKV) infection. ZIKV infection is associated with a wide range of clinical manifestations in human from mild to severe symptoms including abnormal fetal brain development. We found that the antiviral function of TRIM22 plays a crucial role in counterattacking ZIKV infection. Overexpression of TRIM22 protein inhibited ZIKV growth whereas deletion of TRIM22 in host cells increased ZIKV infectivity. Mechanistically, TRIM22, as a functional E3 ubiquitin ligase, promoted the ubiquitination and degradation of ZIKV nonstructural protein 1 (NS1) and nonstructural protein 3 (NS3). Further studies showed that the SPRY domain and Ring domain of TRIM22 played important roles in protein interaction and degradation, respectively. In addition, we found that TRIM22 also inhibited other flaviviruses infection including dengue virus (DENV) and yellow fever virus (YFV). CONCLUSION: Thus, TRIM22 is an ISG with important role in host defense against flaviviruses through binding and degradation of the NS1 and NS3 proteins.

No Exit: China's State Surveillance over People Who Use Drugs.

In China, although drug use is an administrative and not criminal offense, individuals detained by public security authorities are subject to coercive or compulsory "treatment," which can include community-based detoxification and rehabilitation and two years of compulsory isolation. Individuals are also entered into a system called the Drug User Internet Dynamic Control and Early Warning System, or simply the Dynamic Control System. The Dynamic Control System, run by the Ministry of Public Security, acts as an extension of China's drug control efforts by monitoring the movement of people in the system and alerting police when individuals, for example, use their identity documents when registering at a hotel, conducting business at a government office or bank, registering a mobile phone, applying for tertiary education, or traveling. This alert typically results in an interrogation and a drug test by police. This paper seeks to summarize, using published government reports, news articles, and academic papers, what is known about the Dynamic Control System, focusing on the procedures of (1) registration; (2) management; and (3) exit. At each step, people subject to the Dynamic Control System face human rights concerns, especially related to the right to privacy, rights to education and work, and right to health.

Mining of Wheat Pm2 Alleles for Goal-Oriented Marker-Assisted Breeding.

Powdery mildew of wheat, caused by Blumeria graminis f. sp. tritici (Bgt), is a devastating disease that seriously reduces yield and quality worldwide. Utilization of plant resistance genes is an attractive and effective strategy for controlling this disease. Among the reported powdery mildew (Pm) resistance genes, Pm2 exhibits a diverse resistance spectrum among its multiple alleles. It has been widely used in China for resistance breeding for powdery mildew. To mine more Pm2 alleles and clarify their distribution, we screened 33 wheat cultivars/breeding lines carrying Pm2 alleles from 641 wheat genotypes using diagnostic and Pm2-linked markers. To further investigate the relationships within the Pm2 alleles, we compared their resistance spectra, polymorphism of marker alleles and gene sequences, and found that they have identical marker alleles and gene sequences but diverse resistance spectra. In addition, the diagnostic kompetitive allele-specific PCR (KASP) marker, YTU-KASP-Pm2, was developed and was shown to detect all the Pm2 alleles in the different genetic backgrounds. These findings provide valuable information for the distribution and rational use of Pm2 alleles, push forward their marker-assisted breeding (MAS), and hence improve the control of wheat powdery mildew.

Human rights in pandemics: criminal and punitive approaches to COVID-19.

In the early years of the HIV epidemic, many countries passed laws criminalising HIV non-disclosure, exposure and/or transmission. These responses, intended to limit transmission and punish those viewed as 'irresponsible', have since been found to undermine effective HIV responses by driving people away from diagnosis and increasing stigma towards those living with HIV. With the emergence of COVID-19, human rights and public health advocates raised concerns that countries might again respond with criminal and punitive approaches. To assess the degree to which countries adopted such strategies, 51 English-language emergency orders from 39 countries, representing seven world regions, were selected from the COVID-19 Law Lab, a database of COVID-19 related laws from over 190 countries. Emergency orders were reviewed to assess the type of restrictions identified, enforcement mechanisms and compliance with principles outlined in the Siracusa Principles on the Limitation and Derogation Provisions in the International Covenant on Civil and Political Rights, including legality, legitimate aim, proportionality, non-discrimination, limited duration and subject to review. Approximately half of all orders examined included criminal sanctions related to violations of lockdowns. Few orders fully complied with the legal requirements for the limitation of, or derogation from, human rights obligations in public health emergencies. In future pandemics, policymakers should carefully assess the need for criminal and punitive responses and ensure that emergency orders comply with countries' human rights obligations.

ADP-ribosyltransferase PARP11 suppresses Zika virus in synergy with PARP12.

BACKGROUND: Zika virus (ZIKV) infection and ZIKV epidemic have been continuously spreading silently throughout the world and its associated microcephaly and other serious congenital neurological complications poses a significant global threat to public health. Type I interferon response to ZIKV infection in host cells suppresses viral replication by inducing the expression of interferon-stimulated genes (ISGs). METHODS: The study aims to demonstrate the anti-ZIKV mechanism of PARP11. PARP11 knock out and overexpressing A549 cell lines were constructed to evaluate the anti-ZIKV function of PARP11. PARP11-/-, PARP12-/- and PARP11-/-PARP12-/- HEK293T cell lines were constructed to explain the synergistic effect of PARP11 and PARP12 on NS1 and NS3 protein degradation. Western blotting, immunofluorescence and immunoprecipitation assay were performed to illustrate the interaction between PARP11 and PARP12. RESULTS: Both mRNA and protein levels of PARP11 were induced in WT but not IFNAR1-/- cells in response to IFNα or IFNß stimulation and ZIKV infection. ZIKV replication was suppressed in cells expressed PARP11 but was enhanced in PARP11-/- cells. PARP11 suppressed ZIKV independently on itself PARP enzyme activity. PARP11 interacted with PARP12 and promoted PARP12-mediated ZIKV NS1 and NS3 protein degradation. CONCLUSION: We identified ADP-ribosyltransferase PARP11 as an anti-ZIKV ISG and found that it cooperated with PARP12 to enhance ZIKV NS1 and NS3 protein degradation. Our findings have broadened the understanding of the anti-viral function of ADP-ribosyltransferase family members, and provided potential therapeutic targets against viral ZIKV infection.

Analysis of the HNF4A isoform-regulated transcriptome identifies CCL15 as a downstream target in gastric carcinogenesis.

OBJECTIVE: Hepatocyte nuclear factor 4α (HNF4A) has been demonstrated to be an oncogene in gastric cancer (GC). However, the roles of different HNF4A isoforms derived from the 2 different promoters (P1 and P2) and the underlying mechanisms remain obscure. METHODS: The expression and prognostic values of P1- and P2-HNF4A were evaluated in The Cancer Genome Atlas (TCGA) databases and GC tissues. Then, functional assays of P1- and P2-HNF4A were conducted both in vivo and in vitro. High-throughput RNA-seq was employed to profile downstream pathways in P1- and P2-HNF4A-overexpressing GC cells. The expression and gene regulation network of the candidate target genes identified by RNA-seq were characterized based on data mining and functional assays. RESULTS: HNF4A amplification was a key characteristic of GC in TCGA databases, especially for the intestinal type and early stage. Moreover, P1-HNF4A expression was significantly higher in tumor tissues than in adjacent non-tumor tissues (P < 0.05), but no significant differences were found in P2-HNF4A expression (P > 0.05). High P1-HNF4A expression indicated poor prognoses in GC patients (P < 0.01). Furthermore, P1-HNF4A overexpression significantly promoted SGC7901 and BGC823 cell proliferation, invasion and migration in vitro (P < 0.01). Murine xenograft experiments showed that P1-HNF4A overexpression promoted tumor growth (P < 0.05). Mechanistically, RNA-seq showed that the cytokine-cytokine receptor interactions pathway was mostly enriched in P1-HNF4A-overexpressing GC cells. Finally, chemokine (C-C motif) ligand 15 was identified as a direct target of P1-HNF4A in GC tissues. CONCLUSIONS: P1-HNF4A was the main oncogene during GC progression. The cytokine-cytokine receptor interaction pathway played a pivotal role and may be a promising therapeutic target.

Long non-coding RNA CCAT1 sponges miR-490 to enhance cell proliferation and migration of non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer which is the most frequently diagnosed malignancy in China. Colon cancer associated transcript 1 (CCAT1) acts as an oncogene in enhancing tumor progression. However, the effects of CCAT1 in NSCLC remain unclear. The purpose of this study was to explore the role of CCAT1 in NSCLC. METHODS: Wound healing and transwell assays were performed to measure cell migration. RT-qPCR was employed to calculate the mRNA level of CCAT1 and miR-490. RESULTS: High expression of CCAT1 was observed in NSCLC tissues and cells, with low expression of miR-490. CCAT1 promoted the proliferation and metastasis of H1299 and A549 cells, while miR-490 had the opposite effect. CCAT1 could specifically bind to miR-490 and regulate its expression. MiR-490 partially reversed the inhibitory effect of CCAT1 on cell proliferation and metastasis. CONCLUSIONS: The CCAT1/miR-490 molecular axis has been shown to be important for the treatment of NSCLC.