Epidemiological studies of arsenic-exposed populations have provided evidence that arsenic exposure in humans is associated with immunosuppression. Previously, we have reported that arsenite-induced toxicity is associated with the induction of autophagy in human lymphoblastoid cell lines (LCL). Autophagy is a cellular process that functions in the degradation of damaged cellular components, including protein aggregates formed by misfolded or damaged proteins. Accumulation of misfolded or damaged proteins in the endoplasmic reticulum (ER) lumen causes ER stress and activates the unfolded protein response (UPR). In an effort to investigate the mechanism of autophagy induction by arsenite in the LCL model, we examined the potential contribution of ER stress and activation of the UPR. LCL exposed to sodium arsenite for 8-days induced expression of UPR-activated genes, including CHOP and GRP78, at the RNA and the protein level. Evidence for activation of the three arms of the UPR was observed. The arsenite-induced activation of the UPR was associated with an accumulation of protein aggregates containing p62 and LC3, proteins with established roles in the sequestration and autophagic clearance of protein aggregates. Taken together, these data provide evidence that arsenite-induced autophagy is associated with the generation of ER stress, activation of the UPR, and formation of protein aggregates that may be targeted to the lysosome for degradation.
ER stress; Arsenite; Autophagy; Proteotoxicity; Lymphoblastoid cell lines
Extremely hot events (usually involving a few hours at extreme high temperatures in summer) are expected to increase in frequency in temperate regions under global warming. The impact of these events is generally overlooked in insect population prediction, since they are unlikely to cause widespread mortality, however reproduction may be affected by them. In this study, we examined such stress effects in the diamondback moth, Plutella xylostella. We simulated a single extreme hot day (maximum of 40°C lasting for 3, 4 or 5 h) increasingly experienced under field conditions. This event had no detrimental effects on immediate mortality, copulation duration, mating success, longevity or lifetime fecundity, but stressed females produced 21% (after 3 or 4 h) fewer hatched eggs because of a decline in the number and hatching success of eggs laid on the first two days. These negative effects on reproduction were no longer evident in the following days. Male heat exposure led to a similar but smaller effect on fertile egg production, and exposure extended pre-mating period in both sexes. Our results indicate that a single hot day can have detrimental effects on reproduction, particularly through maternal effects on egg hatching, and thereby influence the population dynamics of diamondback moth.
Pediatric primary nephrotic syndrome (PNS) is a chronic disease promoted by metabolic and immune dysfunctions. Peroxisome proliferator-activated receptor (PPAR) polymorphisms have been associated with a variety of metabolic and kidney disorders. We therefore hypothesized that PPAR polymorphisms might be involved in the pathophysiology of PNS. We compared the distributions of the PPAR-γ Pro12Ala and Val290Met, PPAR-γ coactivator-α (PGC-1α) Gly482Ser, and PPAR-α Leu162Val single nucleotide polymorphisms (SNPs) between children with PNS and normal controls and analyzed their correlations with clinical and metabolic indicators and steroid responsiveness. There were no significant differences in distributions of any of the polymorphisms between PNS cases and controls. However, PNS patients with the PPAR-γ (Pro12Ala) PP genotype had significantly higher fasting serum insulin, IgA, and HOMA-IR levels and lower insulin sensitivity than did patients with PA and AA genotypes. Additionally, the PGC-1α (Gly482Ser) A allele was associated with lower CD8+ T-cell counts and higher triglyceride and complement C3 levels compared with the G allele. No polymorphisms were related to hormone sensitivity. These results suggest that the PPAR-γ (Pro12Ala) and PGC-1α (Gly482Ser) SNPs may influence insulin and triglyceride metabolism in children with PNS and may thus be relevant to the prognosis of this chronic condition.
Macrolide resistance rates of Mycoplasma pneumoniae in the Beijing population were as high as 68.9%, 90.0%, 98.4%, 95.4%, and 97.0% in the years 2008 to 2012, respectively. Common macrolide-resistant mobile genetic elements were not detected with any isolate. These macrolide-resistant isolates came from multiple clones rather than the same clone. No massive aggregation of a particular clone was found in a specific period.
Replication of hepatitis B virus (HBV) via protein-primed reverse transcription is initiated by binding of the viral P protein to the conserved ε stem-loop on the pregenomic (pg) RNA. This triggers encapsidation of the complex and the ε-templated synthesis of a short P protein-linked DNA oligonucleotide (priming) for subsequent minus-strand DNA extension. ε consists of a lower and upper stem, a bulge containing the priming template, and an apical loop. The nonhelical subelements are considered important for DNA synthesis and pgRNA packaging whereas the role of the upper stem is not well characterized. Priming itself could until recently not be addressed because in vitro generated HBV P - ε complexes showed no activity. Focussing on the four A residues at the base and tip of the upper ε stem and the two U residues in the loop we first investigated the impact of 24 mutations on viral DNA accumulation in transfected cells. While surprisingly many mutations were tolerated, further analyzing the negatively acting mutations, including in a new cell-free priming system, revealed divergent position-related impacts on pgRNA packaging, priming activity and possibly initiation site selection. This genetic separability implies that the ε RNA undergoes multiple distinct interactions with P protein as pgRNA encapsidation and replication initiation progress, and that the strict conservation of ε in nature may reflect its optimal adaptation to comply with all of them. The data further define the most attractive mutants for future studies, including as decoys for interference with HBV replication.
A total of 201 Mycoplasma pneumoniae clinical isolates from Beijing, China, isolated from 2008 to 2011, were clustered into 16 multiple-locus variable-number tandem-repeat analysis (MLVA) types, of which 6 new MLVA types have never been reported previously. Type 1 isolates based on p1 gene genotyping were mainly MLVA types E, J, P, U, and X. There was no correlation between macrolide-resistant Mycoplasma pneumoniae and their MLVA type.
The role of Th17 cells in cancer patients remains unclear and controversial. In this study, we have analyzed the phenotype of in vitro primed Th17 cells and further characterized their function on the basis of CCR4 and CCR6 expression. We show a novel function for a subset of IL-17 secreting CD4+ T cells, namely CCR4+CCR6+Th17 cells. When cultured together, CCR4+CCR6+Th17 cells suppressed the lytic function, proliferation and cytokine secretion of both antigen specific and CD3/CD28/CD2 stimulated autologous CD8+ T cells. In contrast, CCR4negCCR6+ CD4+ T cells, which also secrete IL-17, did not affect the CD8+ T cells. Suppression of CD8+ T cells by CCR4+CCR6+Th17 cells was partially dependent on TGF-β, since neutralization of TGF-β in cocultures reversed their suppressor function. In addition, we also found an increase in the frequency of CCR4+CCR6+, but not CCR4negCCR6+ Th17 cells in peripheral blood of HCC patients. Our study not only underlies the importance of analysis of subsets within Th17 cells to understand their function, but also suggests Th17 cells as yet another immune evasion mechanism in HCC. This has important implications when studying the mechanisms of carcinogenesis as well as designing effective immunotherapy protocols for patients with cancer.
N-acetylneuraminate pyruvate lyase (NPL) catalyzes N-acetylneuraminic acid, the predominant sialic acid. Microarray analysis of the periimplantation mouse uterine luminal epithelium (LE) revealed Npl being the most downregulated (35×) gene in the LE upon embryo implantation. In natural pregnant mouse uterus, Npl expression increased 56× from gestation day 0.5 (D0.5) to D2.5. In ovariectomized mouse uterus, Npl was significantly upregulated by progesterone (P4) but downregulated by 17β-estradiol (E2). Progesterone receptor (PR) antagonist RU486 blocked the upregulation of Npl in both preimplantation uterus and P4-treated ovariectomized uterus. Npl was specifically localized in the preimplantation D2.5 and D3.5 uterine LE. Since LE is essential for establishing uterine receptivity, it was hypothesized that NPL might play a critical role in uterine function, especially during embryo implantation. This hypothesis was tested in the Npl(−/−) mice. No significant differences were observed in the numbers of implantation sites on D4.5, gestation periods, litter sizes, and postnatal offspring growth between wild type (WT) and Npl(−/−) females from mating with WT males. Npl(−/−)xNpl(−/−) crosses produced comparable little sizes as that from WTxWT crosses. Comparable mRNA expression levels of several genes involved in sialic acid metabolism were observed in D3.5 uterus and uterine LE between WT and Npl(−/−), indicating no compensatory upregulation in the D3.5 Npl(−/−) uterus and LE. This study demonstrates PR-mediated dynamic expression of Npl in the periimplantation uterus and dispensable role of Npl in uterine function and embryo development.
The Hepatitis B Virus (HBV) genome contains four ORFs, S (surface), P (polymerase), C (core) and X. S is completely overlapped by P and as a consequence the overlapping region is subject to distinctive evolutionary constraints compared to the remainder of the genome. Specifically, a non-synonymous substitution in one coding frame may produce a synonymous substitution in the alternative frame, suggesting a possible conflict between requirements for diversifying and purifying forces. To examine how these contrasting requirements are balanced within this region, we investigated the relationship amongst positive selection sites, conserved regions, epitopes and elements of protein structure to consider how HBV balances the contrasting evolutionary pressures.
323 HBV genotype D genome sequences were collected and analyzed to identify sites under positive selection and highly conserved regions. Epitopes sequences were retrieved from previously published experimental studies stored in the Immune Epitope Database. Predicted secondary structures were used to investigate the association between structure and conservation. Entropy was used as a measure of conservation and bivariate logistic regression was used to investigate the relationship between positive selection/conserved sites and epitope/secondary structure regions. Our results indicate: (i) conservation in S is primarily dictated by α-helix elements in the protein structure, (ii) variable residues are mainly located in PreS, the major hydrophilic region (MHR) and the C-terminus, (iii) epitopes in S, which are directly targeted by the host immune system, are significantly associated with sites under positive selection.
The highly variable spacer domain in P, which corresponds to PreS in S, appears to act as a harbor for the accumulation of mutations that can provide flexibility for conformational changes and responding to immune pressure.
PRSS23 and PRSS35 are homologous proteases originally identified in mouse ovaries. In the periimplantation mouse uterus, Prss23 was highly expressed in the preimplantation gestation day 3.5 (D3.5) uterine luminal epithelium (LE). It disappeared from the postimplantation LE and reappeared in the stromal compartment next to the myometrium on D6.5. It was undetectable in the embryo from D4.5 to D6.5 but highly expressed in the embryo on D7.5. Prss35 became detectable in the uterine stromal compartment surrounding the embryo on D4.5 and shifted towards the mesometrial side of the stromal compartment next to the embryo from D5.5 to D7.5. In the ovariectomized uterus, Prss23 was moderately and Prss35 was dramatically downregulated by progesterone and 17β-estradiol. Based on the expression of Prss35 in granulosa cells and corpus luteum of the ovary and the early pregnant uterus, we hypothesized that PRSS35 might play a role in female reproduction, especially in oocyte development, ovulation, implantation, and decidualization. This hypothesis was tested in Prss35(−/−) mice, which proved otherwise. Between wild type (WT) and Prss35(−/−) mice, superovulation of immature females produced comparable numbers of cumulus-oocyte complexes; there were comparable numbers of implantation sites detected on D4.5 and D7.5; there were no obvious differences in the expression of implantation and decidualization marker genes in D4.5 or D7.5 uteri. Comparable mRNA expression levels of a few known protease-related genes in the WT and Prss35(−/−) D4.5 uteri indicated no compensatory upregulation. Comparable litter sizes from WT × WT and Prss35(−/−)× Prss35(−/−) crosses suggested that Prss35 gene was unessential for fertility and embryo development. Prss35 gene has been linked to cleft lip/palate in humans. However, no obvious such defects were observed in Prss35(−/−) mice. This study demonstrates the distinct expression of Prss23 and Prss35 in the periimplantation uterus and the dispensable role of Prss35 in fertility and embryo development.
GJB2 mutation was frequent in sporadic outpatients and its mutation frequency was significant higher in the prelingual group than in the postlingual group, whereas the mutation of mtDNA A1555G and SLC26A4 was very rare in Chinese sporadic outpatients with nonsyndromic sensorineural hearing loss (NSHL). Standard and comprehensive inclusion and grouping criteria are necessary for epidemiological studies of deafness-related gene mutations.
This study aimed to examine the mutations of the three common deafness genes GJB2, SLC26A4, and mtDNA A1555G in Chinese sporadic outpatients withNSHLandtodiscussthefactorsthatinfluencethedetection accuracyofmutationfrequencies.
A total of 473 sporadic NSHL patients without any type of inner ear malformation, including both prelingual and postlingual groups were enrolled in this study. Three genes of mtDNA A1555G, GJB2, and SLC26A4 were screened for mutation in our study cohort. A chi-square test was performed to compare mutation frequencies between prelingual and postlingual groups.
The mutation frequencies of MtDNA A1555G, GJB2, and SLC26A4 were 1.63%, 13.63%, and 0%, respectively, in our study cohort. The mutational hot spot of GJB2 was c.235delC, whose allele frequency was 12.68% in sporadic outpatients. Mutation frequency of GJB2 in the prelingual group was significantly higher than in the postlingual group (p < 0.05).
Genetic testing; deafness genes
The role of interleukin-17 (IL-17)-secreting CD4+ T (Th17) cells in cancer is under intense investigation. We have demonstrated that CCR4+CCR6+ Th17 cells not only are increased in the peripheral blood of patients affected by hepatocellular carcinoma, but also suppress CD8+ T-cell functions in vitro. These results suggest that Th17 cells may exert immunosuppressive functions in hepatocellular carcinoma.
CCR4; CCR6; IL-17; cancer; liver
TCRαβ+ CD4−CD8−NK− double negative T cells (DN T cells) can act as regulatory T cells to inhibit allograft rejection and autoimmunity. Their role in graft-versus-host disease and mechanisms of suppression remain elusive. In this study, we demonstrate that DN T cells can inhibit CD4+ T cell-mediated GVHD in a semi-allogeneic model of bone marrow transplantation. Furthermore, we present evidence of a novel autocrine IFNγ signaling pathway in Fas-deficient C57BL/6.lpr (B6.lpr) DN T cells. B6.lpr DN T cells lacking IFNγ or its receptor were impaired in their ability to suppress syngeneic CD4+ T cells responding to alloantigen stimulation both in vitro and in vivo. Autocrine IFNγ signaling was required for sustained B6.lpr DN T cell IFNγ secretion in vivo and for upregulation of surface Fas ligand expression during TCR stimulation. Fas ligand (FasL) expression by B6.lpr DN T cells permitted lysis of activated CD4+ T cells and was required for suppression of GVHD. Collectively, our data indicate that DN T cells can inhibit GVHD and that IFNγ plays a critical autocrine role in controlling the regulatory function of B6.lpr DN T cells.
MICs of eight antibiotics were detected with 40 Chinese Mycoplasma pneumoniae isolates. Thirty-eight isolates (95%) were macrolide resistant. Each macrolide-resistant isolate harbored an A2063G or A2064G point mutation in the 23S rRNA gene. All 40 isolates (100%) were type I strains, but they might have originated from different clones.
The World Bank Loan Project (WBLP) for controlling schistosomiasis in China was implemented during 1992–2001. Its short-term impact has been assessed from non-spatial perspective, but its long-term impact remains unclear and a spatial evaluation has not previously been conducted. Here we compared the spatial distribution of schistosomiasis risk using national datasets in the lake and marshland regions from 1999–2001 and 2007–2008 to evaluate the long-term impact of WBLP strategy on China's schistosomiasis burden.
A hierarchical Poisson regression model was developed in a Bayesian framework with spatially correlated and uncorrelated heterogeneities at the county-level, modeled using a conditional autoregressive prior structure and a spatially unstructured Gaussian distribution, respectively. There were two important findings from this study. The WBLP strategy was found to have a good short-term impact on schistosomiasis control, but its long-term impact was not ideal. It has successfully reduced the morbidity of schistosomiasis to a low level, but can not contribute further to China's schistosomiasis control because of the current low endemic level. A second finding is that the WBLP strategy could not effectively compress the spatial distribution of schistosomiasis risk. To achieve further reductions in schistosomiasis-affected areas, and for sustainable control, focusing on the intermediate host snail should become the next step to interrupt schistosomiasis transmission within the two most affected regions surrounding the Dongting and Poyang Lakes. Furthermore, in the lower reaches of the Yangtze River, the WBLP's morbidity control strategy may need to continue for some time until snails in the upriver provinces have been well controlled.
It is difficult to further reduce morbidity due to schistosomiasis using a chemotherapy-based control strategy in the lake and marshland regions of China because of the current low endemic levels of infection. The future control strategy for schistosomiasis should instead focus on a snail-based integrated control strategy to maintain the program achievements and sustainably reduce the burden of schistosomiasis in China.
Schistosomiasis japonica is an important disease in China with a documented history of more than 2,100 years. The World Bank Loan Project (WBLP) implemented during 1992–2001 contributed greatly to China's schistosomiasis control. This study shows that the long-term impact of WBLP strategy on schistosomiasis control was not ideal. It can only maintain the morbidity of schistosomiasis at a low level, but can not reduce it further. Also, the WBLP strategy could not effectively compress the spatial distribution of schistosomiasis risk. To achieve further reductions in schistosomiasis-affected areas, and for sustainable control, focusing on controlling the intermediate host snail in the lake and marshland regions was suggested to be the next step to interrupt schistosomiasis transmission within the two most affected regions surrounding the Dongting and Poyang Lakes. While in the lower reaches of the Yangtze River, the WBLP's morbidity control strategy may need to continue for some time until snails in the upriver provinces have been well controlled.
Protein glycosylation alteration is typically employed by various viruses for escaping immune pressures from their hosts. Our previous work had shown that not only the increase of glycosylation sites (glycosites) numbers, but also glycosite migration might be involved in the evolution of human seasonal influenza H1N1 viruses. More importantly, glycosite migration was likely a more effectively alteration way for the host adaption of human influenza H1N1 viruses. In this study, we provided more bioinformatics and statistic evidences for further predicting the significant biological functions of glycosite migration in the host adaptation of human influenza H1N1 viruses, by employing homology modeling and in silico protein glycosylation of representative HA and NA proteins as well as amino acid variability analysis at antigenic sites of HA and NA. The results showed that glycosite migrations in human influenza viruses have at least five possible functions: to more effectively mask the antigenic sites, to more effectively protect the enzymatic cleavage sites of neuraminidase (NA), to stabilize the polymeric structures, to regulate the receptor binding and catalytic activities and to balance the binding activity of hemagglutinin (HA) with the release activity of NA. The information here can provide some constructive suggestions for the function research related to protein glycosylation of influenza viruses, although these predictions still need to be supported by experimental data.
The p1 genes of 60 Mycoplasma pneumoniae clinical isolates were sequenced and compared to previously reported p1 gene sequences. An AGT trinucleotide variable-number tandem repeat was identified that ranged in copy number from 5 to 14 among the isolates. In addition, a novel p1 gene variant named 2c was identified in 6 of the isolates.
The transcription factor Nrf2 has emerged as a master regulator of cellular redox homeostasis. As an adaptive response to oxidative stress, Nrf2 activates the transcription of a battery of genes encoding antioxidants, detoxification enzymes, and xenobiotic transporters by binding the cis-antioxidant response element in the promoter regions of genes. The magnitude and duration of inducible Nrf2 signaling is delicately controlled at multiple levels by Keap1, which targets Nrf2 for redox-sensitive ubiquitin-mediated degradation in the cytoplasm and exports Nrf2 from the nucleus. However, it is not clear how Keap1 gains access to the nucleus. In this study, we show that Keap1 is constantly shuttling between the nucleus and the cytoplasm under physiological conditions. The nuclear import of Keap1 requires its C-terminal Kelch domain and is independent of Nrf1 and Nrf2. We have determined that importin α7, also known as karyopherin α6 (KPNA6), directly interacts with the Kelch domain of Keap1. Overexpression of KPNA6 facilitates Keap1 nuclear import and attenuates Nrf2 signaling, whereas knockdown of KPNA6 slows down Keap1 nuclear import and enhances the Nrf2-mediated adaptive response induced by oxidative stress. Furthermore, KPNA6 accelerates the clearance of Nrf2 protein from the nucleus during the postinduction phase, therefore promoting restoration of the Nrf2 protein to basal levels. These findings demonstrate that KPNA6-mediated Keap1 nuclear import plays an essential role in modulating the Nrf2-dependent antioxidant response and maintaining cellular redox homeostasis.
Influenza virus typically alters protein glycosylation in order to escape immune pressure from hosts and hence to facilitate survival in different host environments. In this study, the patterns and conservation of glycosylation sites on HA and NA of influenza A/H1N1 viruses isolated from various hosts at different time periods were systematically analyzed, by employing a new strategy combining genome-based glycosylation site prediction and 3D modeling of glycoprotein structures, for elucidation of the modes and laws of glycosylation site alteration in the evolution of influenza A/H1N1 viruses. The results showed that influenza H1N1 viruses underwent different alterations of protein glycosylation in different hosts. Two alternative modes of glycosylation site alteration were involved in the evolution of human influenza virus: One was an increase in glycosylation site numbers, which mainly occurred with high frequency in the early stages of evolution. The other was a change in the positional conversion of the glycosylation sites, which was the dominating mode with relatively low frequency in the later evolutionary stages. The mechanisms and possibly biological functions of glycosylation site alteration for the evolution of influenza A/H1N1 viruses were also discussed. Importantly, the significant role of positional alteration of glycosylation sites in the host adaptation of influenza virus was elucidated. Although the results still need to be supported by experimental data, the information here may provide some constructive suggestions for research into the glycosylation of influenza viruses as well as even the design of surveillance and the production of viral vaccines.
Type II endometrial cancer, which mainly presents as serous and clear cell types, has proved to be the most malignant and recurrent carcinoma among various female genital malignancies. The transcription factor, Nrf2, was first described as having chemopreventive activity. Activation of the Nrf2-mediated cellular defense response protects cells against the toxic and carcinogenic effects of environmental insults by upregulating an array of genes that detoxify reactive oxygen species (ROS) and restore cellular redox homeostasis. However, the cancer-promoting role of Nrf2 has recently been revealed. Nrf2 is constitutively upregulated in several types of human cancer tissues and cancer cell lines. Furthermore, inhibition of Nrf2 expression sensitizes cancer cells to chemotherapeutic drugs. In this study, the constitutive level of Nrf2 was compared in different types of human endometrial tumors. It was found that Nrf2 was highly expressed in endometrial serous carcinoma (ESC), whereas complex hyperplasia (CH) and endometrial endometrioid carcinoma (EEC) had no or marginal expression of Nrf2. Likewise, the ESC derived SPEC-2 cell line had a higher level of Nrf2 expression and was more resistant to the toxic effects of cisplatin and paclitaxel than that of the Ishikawa cell line, which was generated from EEC. Silencing of Nrf2 rendered SPEC-2 cells more susceptible to chemotherapeutic drugs while it had a limited effect on Ishikawa cells. Inhibition of Nrf2 expression by overexpressing Keap1 sensitized SPEC-2 cells or SPEC-2-derived xenografts to chemotherapeutic treatments using both cell culture and SCID mouse models. Collectively, we provide a molecular basis for the use of Nrf2 inhibitors to increase the efficacy of chemotherapeutic drugs and to combat chemoresistance, the biggest obstacle in chemotherapy.
Nrf2; chemoresistance; and endometrial cancer
BWI-1 (buckwheat trypsin inhibitor), a member of the potato inhibitor I family, suppresses the growth of T-acute lymphoblastic leukemia cells and induces apoptosis in human solid tumor cell lines. Here, we report the crystal structure of rBTI (recombinant buckwheat trypsin inhibitor), a recombinant protein of BWI-1, at 1.84 Å resolution and the structure of rBTI in complex with bovine trypsin at 2.26 Å resolution. A conformational change of Trp53 at the P8′ position in rBTI was observed upon its binding to trypsin, which is not seen in other members of the potato inhibitor I family reported previously. The role of the P8′ residue in the potato inhibitor I family was examined by measuring the association and dissociation rates of four rBTI mutants with different substitutions at the P2 and P8′ positions when binding to trypsin. One of the mutants, P44T, was found to be a much stronger inhibitor than wild-type rBTI, with a picomolar (pM) dissociation constant. Our results could provide valuable insights for designing a new rBTI-based antitumor drug in the future.
Au-Si nano-particle-decorated silicon nanowire arrays have been fabricated by Au film deposition on silicon nanowire array substrates and then post-thermal annealing under hydrogen atmosphere. Field emission measurements illustrated that the turn-on fields of the non-annealed Au-coated SiNWs were 6.02 to 7.51 V/μm, higher than that of the as-grown silicon nanowires, which is about 5.01 V/μm. Meanwhile, after being annealed above 650°C, Au-Si nano-particles were synthesized on the top surface of the silicon nanowire arrays and the one-dimensional Au-Si nano-particle-decorated SiNWs had a much lower turn-on field, 1.95 V/μm. The results demonstrated that annealed composite silicon nanowire array-based electron field emitters may have great advantages over many other emitters.
In response to stress, cells can utilize several cellular processes, such as autophagy, which is a bulk-lysosomal degradation pathway, to mitigate damages and increase the chances of cell survival. Deregulation of autophagy causes upregulation of p62 and the formation of p62-containing aggregates, which are associated with neurodegenerative diseases and cancer. The Nrf2-Keap1 pathway functions as a critical regulator of the cell's defense mechanism against oxidative stress by controlling the expression of many cellular protective proteins. Under basal conditions, Nrf2 is ubiquitinated by the Keap1-Cul3-E3 ubiquitin ligase complex and targeted to the 26S proteasome for degradation. Upon induction, the activity of the E3 ubiquitin ligase is inhibited through the modification of cysteine residues in Keap1, resulting in the stabilization and activation of Nrf2. In this current study, we identified the direct interaction between p62 and Keap1 and the residues required for the interaction have been mapped to 349-DPSTGE-354 in p62 and three arginines in the Kelch domain of Keap1. Accumulation of endogenous p62 or ectopic expression of p62 sequesters Keap1 into aggregates, resulting in the inhibition of Keap1-mediated Nrf2 ubiquitination and its subsequent degradation by the proteasome. In contrast, overexpression of mutated p62, which loses its ability to interact with Keap1, had no effect on Nrf2 stability, demonstrating that p62-mediated Nrf2 upregulation is Keap1 dependent. These findings demonstrate that autophagy deficiency activates the Nrf2 pathway in a noncanonical cysteine-independent mechanism.
Highly pathogenic avian influenza subtype H5N1 is a zoonotic disease and control of the disease is one of the highest priority in global health. Disease surveillance systems are valuable data sources for various researches and management projects, but the data quality has not been paid much attention in previous studies. Based on data from two commonly used databases (Office International des Epizooties (OIE) and Food and Agriculture Organization of the United Nations (FAO)) of global HPAI H5N1 outbreaks during the period of 2003–2009, we examined and compared their patterns of temporal, spatial and spatio-temporal distributions for the first time. OIE and FAO data showed similar trends in temporal and spatial distributions if they were considered separately. However, more advanced approaches detected a significant difference in joint spatio-temporal distribution. Because of incompleteness for both OIE and FAO data, an integrated dataset would provide a more complete picture of global HPAI H5N1 outbreaks. We also displayed a mismatching profile of global HPAI H5N1 outbreaks and found that the degree of mismatching was related to the epidemic severity. The ideas and approaches used here to assess spatio-temporal data on the same disease from different sources are useful for other similar studies.