Genome-wide association studies (GWASs) have identified more than 150 loci associated with blood lipid and cholesterol levels; however, the functional and molecular mechanisms for many associations are unknown. We examined the functional regulatory effects of candidate variants at the GALNT2 locus associated with high-density lipoprotein cholesterol (HDL-C). Fine-mapping and conditional analyses in the METSIM study identified a single locus harboring 25 noncoding variants (r(2) > 0.7 with the lead GWAS variants) strongly associated with total cholesterol in medium-sized HDL (e.g., rs17315646, p = 3.5 × 10(-12)). We used luciferase reporter assays in HepG2 cells to test all 25 variants for allelic differences in regulatory enhancer activity. rs2281721 showed allelic differences in transcriptional activity (75-fold [T] versus 27-fold [C] more than the empty-vector control), as did a separate 780-bp segment containing rs4846913, rs2144300, and rs6143660 (49-fold [AT(-) haplotype] versus 16-fold [CC(+) haplotype] more). Using electrophoretic mobility shift assays, we observed differential CEBPB binding to rs4846913, and we confirmed this binding in a native chromatin context by performing chromatin-immunoprecipitation (ChIP) assays in HepG2 and Huh-7 cell lines of differing genotypes. Additionally, sequence reads in HepG2 DNase-I-hypersensitivity and CEBPB ChIP-seq signals spanning rs4846913 showed significant allelic imbalance. Allelic-expression-imbalance assays performed with RNA from primary human hepatocyte samples and expression-quantitative-trait-locus (eQTL) data in human subcutaneous adipose tissue samples confirmed that alleles associated with increased HDL-C are associated with a modest increase in GALNT2 expression. Together, these data suggest that at least rs4846913 and rs2281721 play key roles in influencing GALNT2 expression at this HDL-C locus.

An intronic GGGGCC hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene was considered as the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in Caucasian populations. Using repeat-primed polymerase chain reaction analysis and Southern blotting methods, we assessed the frequency and size of hexanucleotide repeat expansion in a cohort of 918 sporadic ALS (SALS) patients and 632 control individuals of Han Chinese origin. We identified 8 (0.87%) of the SALS patients and none of control individuals as carriers of C9orf72 expansions with 700-3500 repeats. A comprehensive neuropsychological battery was conducted on 4 expansion-positive ALS patients, where 3 patients were found to have cognitive impairment. All expansion-positive patients were genotyped for the previously reported 20 single-nucleotide polymorphism (SNP) risk haplotypes on chromosome 9p21. Among them, 13 SNP risk haplotypes were shared in all expansion carriers, suggesting a common founder from European ancestry. Further meta-analysis demonstrated that the intermediate expansion size with 24-30 repeats, rare in both patients and controls, were significantly associated with the risk for ALS. To our knowledge, this is the first study to identify a proportion of Chinese SALS patients carrying this pathologic expansion of up to ∼3500 repeats and to completely elaborate the 20-SNP risk haplotypes in Chinese expansion-positive patients, providing indispensable evidence for the origin, geographical range, and population prevalence of the C9orf72-associated ALS.

Geese, as aquatic birds, are an important natural reservoir of avian influenza virus (AIV). To characterize the innate antiviral immune response against AIV H9N2 strain infection in geese as well as the probable relationship between the expression of immune-related genes and the distribution of viral antigens, we investigated the levels of immune-related gene transcription both in AIV H9N2 strain-infected geese and in vitro. The patterns of viral location and the tissue distribution of CD4- and CD8α-positive cells were concurrently detected by immunohistochemical staining, which revealed respiratory and digestive organs as the primary sites of antigen-positive signals. Average AIV H9N2 viral loads were detected in the feces, Harderian gland (HG), and trachea, where higher copy numbers were detected compared with the rectum. Our results suggested the strong induction of proinflammatory cytokine expression compared with interferons (IFNs). Notably, in most tissues from the AIV H9N2 strain-infected birds, IFNα and IFNγ gene transcripts were differentially expressed. However, inverse changes in IFNα and IFNγ expression after AIV H9N2 strain infection were observed in vitro. Taken together, the results suggest that AIV H9N2 is widely distributed in multiple tissues, efficiently induces inflammatory cytokines in the HG and spleen of goslings and inversely influences type I and II IFN expression both in vivo and in vitro. The findings of this study further our understanding of host defense mechanisms and the pathogenesis of the H9N2 influenza virus in geese.

Long noncoding RNA (lncRNA) plays pivotal roles in cancer development. To date, only a small number of lncRNAs have been characterized at functional level. Here, we discovered a novel lncRNA termed GAS5-AS1 as a tumor suppressor in non-small cell lung cancer (NSCLC). The expression of GAS5-AS1 in NSCLC tumors was much lower than that in the adjacent normal lung tissues. The reduced GAS5-AS1 was significantly correlated with larger tumors, higher TNM stages, and lymph node metastasis in NSCLC patients. While ectopic expression or specific knockdown of GAS5-AS1 had no effect on proliferation, cell cycle progression, and apoptosis, it dramatically decreased or increased, respectively, NSCLC cell migration and invasion. Overexpression of GAS5-AS1 in NSCLC cells reduced a cohort of molecules (ZEB1, N-cadherin, Vimentin, and/or Snail1) critical for epithelial-mesenchymal transition (EMT). Furthermore, the DNA demethylating agent 5-aza-2-deoxycytidine failed to upregulate GAS5-AS1 in NSCLC cells, whereas the pan-HDAC inhibitors panobinostat and SAHA significantly induced GAS5-AS1 in a dose-dependent manner. In addition, GAS5-AS1 can be upregulated by specific knockdown of HDAC1 or HDAC3. Collectively, our data suggest that histone modifications play a major role leading to epigenetic silencing of GAS5-AS1 in NSCLC and subsequently promote tumor metastasis via upregulation of several key EMT markers.

Previous studies have drawn attention to dendritic cell (DC) vaccines; particularly the application of the tumor-associated antigen-targeted DC vaccine. The present study analyzed DCs derived from a normal individual and pulsed the cells with heat shock protein 70 peptide (Hsp70) and/or hepatitis B virus x antigen (HBxAg), a hepatocellular carcinoma (HCC)-associated antigen. It was then investigated whether this method of vaccination induced strong therapeutic antitumor immunity. The results revealed that the Hsp70/HBxAg complex-activated phenotype improves the functional maturation of DCs compared with using Hsp70 or HBxAg alone. Compared with either Hsp70 or HBxAg alone, matured DCs pulsed with the Hsp70/HBxAg complex stimulated a high level of autologous T-cell proliferation and induced HCC-specific cytotoxic T lymphocytes, which specifically killed HCC cells through a major histocompatibility complex class I mechanism. These results indicated that a vaccination therapy using DCs co-pulsed with the Hsp70/HBxAg complex is an effective strategy for immunotherapy and may offer a useful approach to protect against HCC.

The role of FEN1 genetic variants on gallstone and gallbladder cancer susceptibility is unknown. FEN1 SNPs were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method in blood samples from 341 gallbladder cancer patients and 339 healthy controls. The distribution of FEN1-69G > A genotypes among controls (AA, 20.6%; GA, 47.2% and GG 32.2%) was significantly different from that among gallbladder cancer cases (AA, 11.1%; GA, 48.1% and GG, 40.8%), significantly increased association with gallbladder cancer was observed for subjects with both the FEN1-69G > A GA (OR = 1.73, 95% CI = 1.01-2.63) and the FEN1-69G > A GG (OR = 2.29, 95% CI = 1.31-3.9). The distribution of FEN1 -4150T genotypes among controls (TT, 21.8%;GT, 49.3% and GG 28.9%) was significantly different from that among gallbladder cancer cases (TT, 12.9%; GT, 48.4% and GG 38.7%), significantly increased association with gallbladder cancer was observed for subjects with both the FEN1-4150T GT(OR = 1.93, 95% CI = 1.04-2.91) and the FEN1-4150T GG(OR = 2.56, 95% CI = 1.37-5.39). A significant trend towards increased association with gallbladder cancer was observed with potentially higher-risk FEN1-69G > A genotypes (P < 0.001, χ2 trend test) and FEN14150G > T (P < 0.001, χ2 trend test) in gallstone presence but not in gallstone absence (P = 0.81, P = 0.89, respectively). In conclusion, this study revealed firstly that FEN1 polymorphisms and haplotypes are associated with gallbladder cancer risk.

Ampelopsin (APL), a major bioactive constituent of Ampelopsis grossedentata, exerts a number of biological effects. Here, we explored the anti-diabetic activity of APL and elucidate the underlying mechanism of this action. In palmitate-induced insulin resistance of L6 myotubes, APL treatment markedly up- regulated phosphorylated insulin receptor substrate-1 and protein kinase B, along with a corresponding increase of glucose uptake capacity. APL treatment also increased expressions of fibroblast growth factor (FGF21) and phosphorylated adenosine 5'-monophosphate -activated protein kinase (p-AMPK), however inhibiting AMPK by Compound C or AMPK siRNA, or blockage of FGF21 by FGF21 siRNA, obviously weakened APL -induced increases of FGF21 and p-AMPK as well as glucose uptake capacity in palmitate -pretreated L6 myotubes. Furthermore, APL could activate PPAR γ resulting in increases of glucose uptake capacity and expressions of FGF21 and p-AMPK in palmitate -pretreated L6 myotubes, whereas all those effects were obviously abolished by addition of GW9662, a specific inhibitor of peroxisome proliferator- activated receptor -γ (PPARγ), and PPARγsiRNA. Using molecular modeling and the luciferase reporter assays, we observed that APL could dock with the catalytic domain of PPARγ and dose-dependently up-regulate PPARγ activity. In summary, APL maybe a potential agonist of PPARγ and promotes insulin sensitization by activating PPARγ and subsequently regulating FGF21- AMPK signaling pathway. These results provide new insights into the protective health effects of APL, especially for the treatment of Type 2 diabetes mellitus.

Remyelination is the generation of new myelin sheaths after injury facilitated by processes of differentiating oligodendrocyte precursor cells (OPCs). Although this repair phenomenon occurs in lesions of multiple sclerosis patients, many lesions fail to completely remyelinate. A number of factors have been identified that contribute to remyelination failure, including the upregulated chondroitin sulfate proteoglycans (CSPGs) that comprise part of the astrogliotic scar. We show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. We introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice. Preventing CSPG deposition into the lesion microenvironment may be a useful strategy to promote repair in multiple sclerosis and other neurological disorders.

Epithelial ovarian cancer (EOC) is the most deadly of the gynecological cancers. New approaches and better tools for monitoring treatment efficacy and disease progression of EOC are required. In this study, metabolomics using rapid resolution liquid chromatography mass spectrometry was applied to a systematic investigation of metabolic changes in response to advanced EOC, surgery and recurrence. The results revealed considerable metabolic differences between groups. Moreover, 37, 30, and 26 metabolites were identified as potential biomarkers for primary, surgical and recurrent EOC, respectively. Primary EOC was characterized by abnormal lipid metabolism and energy disorders. Oxidative stress and surgical efficacy were clear in the post-operative EOC patients. Recurrent EOC patients showed increased amino acid and lipid metabolism compared with primary EOC patients. After cytoreductive surgery, eight metabolites (e.g. l-kynurenine, retinol, hydroxyphenyllactic acid, 2-octenoic acid) corrected towards levels of the control group, and four (e.g. hydroxyphenyllactic acid, 2-octenoic acid) went back again to primary EOC levels after disease relapse. In conclusion, this study delineated metabolic changes in response to advanced EOC, surgery and recurrence, and identified biomarkers that could facilitate both understanding and monitoring of EOC development and progression.

Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Prolonged cancer treatment will induce the development of acquired resistance to EGFR TKI. Here we investigate the effects of two novel liver x receptor (LXR) ligands (T0901317 or GW3965) on the development of acquired resistance to an EGFR TKI gefitinib. We observed known mechanisms of acquired resistance to EGFR TKI, including the EGFR T790M mutation, MET gene amplification and loss of PTEN in the gefitinib-resistant HCC827-8-1 cells. However, we found expression of MET was lower in HCC827-8-1 cells than in HCC827 cells. T0901317 or GW3965 inhibited Akt activation and sensitized HCC827-8-1 cells to gefitinib-induced cytotoxicity. In contrast, LXR ligands alone had no significant effect on HCC827-8-1 cells. In conclusion, this combined treatment may be of interest for treatment of lung adenocarcinomas harboring EGFR mutations and acquired resistance to gefitinib.

The chemokine (C-X-C motif) ligand 1 (CXCL1) regulates tumor-stromal interactions and tumor invasion. However, the precise role of CXCL1 on gastric tumor growth and patient survival remains unclear. In the current study, protein expressions of CXCL1, vascular endothelial growth factor (VEGF) and phospho-signal transducer and activator of transcription 3 (p-STAT3) in primary tumor tissues from 98 gastric cancer patients were measured by immunohistochemistry (IHC). CXCL1 overexpressed cell lines were constructed using Lipofectamine 2000 reagent or lentiviral vectors. Effects of CXCL1 on VEGF expression and local tumor growth were evaluated in vitro and in vivo. CXCL1 was positively expressed in 41.4% of patients and correlated with VEGF and p-STAT3 expression. Higher CXCL1 expression was associated with advanced tumor stage and poorer prognosis. In vitro studies in AGS and SGC-7901 cells revealed that CXCL1 increased cell migration but had little effect on cell proliferation. CXCL1 activated VEGF signaling in gastric cancer (GC) cells, which was inhibited by STAT3 or chemokine (C-X-C motif) receptor 2 (CXCR2) blockade. CXCL1 also increased p-STAT3 expression in GC cells. In vivo, CXCL1 increased xenograft local tumor growth, phospho-Janus kinase 2 (p-JAK2), p-STAT3 levels, VEGF expression and microvessel density. These results suggested that CXCL1 increased local tumor growth through activation of VEGF signaling which may have mechanistic implications for the observed inferior GC survival. The CXCL1/CXCR2 pathway might be potent to improve anti-angiogenic therapy for gastric cancer.

Several reports have suggested a possible association between the interleukin (IL)-8-251A/T single-nucleotide polymorphism (SNP) and the susceptibility to coronary artery disease (CAD). Due to inconclusive results of the studies so far, we conducted a meta-analysis to systematically summarize the studies on the association between this SNP and CAD risk. A systematic literature search identified 9 case-control studies (3752 cases and 4219 controls) on the IL-8-251A/T polymorphism. We observed a significant association between different genetic forms of -251A/T SNP and CAD risk, like the allele model (A vs T: odds ratio [OR] 1.14, 95% confidence interval [CI] 1.02-1.27, P = .02), dominant model (AA + AT vs TT: OR 1.20, 95% CI 1.01-1.43, P = .042), recessive model (AA vs AT + TT: OR 1.15, 95% CI 1.03-1.27, P = .01), and homozygous model (AA vs TT: OR 1.26, 95% CI 1.01-1.56, P = .037), whereas the heterozygote model did not show any significant association (AT vs TT: OR 1.16, 95% CI 0.98-1.38, P = .091). Furthermore, significant heterogeneity was observed among studies in terms of all genetic models, except the recessive model. Analysis of the ethnic subgroups revealed a significantly higher risk of CAD in the East Asian population carrying this SNP, and the heterogeneity among the studies regarding the East Asian population was decreased after subgroup analysis. The results of this meta-analysis suggest that the IL-8-251A/T SNP may increase the risk of CAD, especially in people of East Asian ethnicity. Further large-scale, multicenter epidemiological studies are warranted to validate this finding.

Myeloid-derived suppressor cells (MDSCs) are key players in immune evasion, tumor progression and metastasis. MDSCs accumulate under various pathological states and fall into two functionally and phenotypically distinct subsets that have been identified in humans and mice: polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. As dogs are an excellent model for human tumor development and progression, we set out to identify PMN-MDSCs and M-MDSCs in clinical canine oncology patients. Canine hypodense MHC class II-CD5-CD21-CD11b+ cells can be subdivided into polymorphonuclear (CADO48A+CD14-) and monocytic (CADO48A-CD14+) MDSC subsets. The transcriptomic signatures of PMN-MDSCs and M-MDSCs are distinct, and moreover reveal a statistically significant similarity between canine and previously published human PMN-MDSC gene expression patterns. As in humans, peripheral blood frequencies of canine PMN-MDSCs and M-MDSCs are significantly higher in dogs with cancer compared to healthy control dogs (PMN-MDSCs: p < 0.001; M-MDSCs: p < 0.01). By leveraging the power of evolution, we also identified additional conserved genes in PMN-MDSCs of multiple species that may play a role in MDSC function. Our findings therefore validate the dog as a model for studying MDSCs in the context of cancer.

Hepatitis A virus is one of five types of hepatotropic viruses that cause human liver disease. A similar liver disease is also identified in ducks caused by Duck Hepatitis A virus (DHAV). Notably, many types of hepatotropic viruses can be detected in urine. However, how those viruses enter into the urine is largely unexplored. To elucidate the potential mechanism, we used the avian hepatotropic virus to investigate replication strategies and immune responses in kidney until 280 days after infection. Immunohistochemistry and qPCR were used to detect viral distribution and copies in the kidney. Double staining of CD4+ or CD8+ T cells and virus and qPCR were used to investigate T cell immune responses and expression levels of cytokines. Histopathology was detected by standard HE staining. In this study, viruses were persistently located at scattered renal tubules. No CD4+ or CD8+ T cells were recruited to the kidney, which was only accompanied by transient cytokine storms. In conclusion, the extremely scattered infection was the viral strategy to escape host immunity and may persistently shed virus into urine. The deletion of Th or Tc cell responses and transient cytokine storms indeed provide an advantageous renal environment for their persistent survival.

Endophytic fungal communities of Dysphania ambrosioides, a hyperaccumulator growing at two Pb-Zn-contaminated sites, were investigated through culture-dependent and culture-independent approaches. A total of 237 culturable endophytic fungi (EF) were isolated from 368 tissue (shoot and roots) segments, and the colonization rate (CR) ranged from 9.64% to 65.98%. The isolates were identified to 43 taxa based on morphological characteristics and rDNA ITS sequence analysis. Among them, 13 taxa (30.23%) were common in plant tissues from both sites; however, dominant EF were dissimilar. In culture-dependent study, 1989 OTUs were obtained through Illumina Miseq sequencing, and dominant EF were almost same in plant tissues from both sites. However, some culturable EF were not observed in total endophytic communities. We suggest that combination of both culture-dependent and culture-independent methods will provide more chances for the precise estimation of endophytic fungal community than using either of them. The tissue had more influence on the culturable fungal community structure, whereas the location had more influence on the total fungal community structure (including culturable and unculturable). Both culture-dependent and culture-independent studies illustrated that endophytic fungal communities of D. ambrosioides varied across the sites, which suggested that HM concentration of the soil may have some influence on endophytic fungal diversity.

Efficient conversion of cellulosic sugars in cellulosic hydrolysates is important for economically viable production of biofuels from lignocellulosic biomass, but the goal remains a critical challenge. The present study reports a new approach for simultaneous fermentation of cellobiose and xylose by using the co-culture consisting of recombinant Saccharomyces cerevisiae specialist strains. The co-culture system can provide competitive advantage of modularity compared to the single culture system and can be tuned to deal with fluctuations in feedstock composition to achieve robust and cost-effective biofuel production. This study characterized fermentation kinetics of the recombinant cellobiose-consuming S. cerevisiae strain EJ2, xylose-consuming S. cerevisiae strain SR8, and their co-culture. The motivation for kinetic modeling was to provide guidance and prediction of using the co-culture system for simultaneous fermentation of mixed sugars with adjustable biomass of each specialist strain under different substrate concentrations. The kinetic model for the co-culture system was developed based on the pure culture models and incorporated the effects of product inhibition, initial substrate concentration and inoculum size. The model simulations were validated by results from independent fermentation experiments under different substrate conditions, and good agreement was found between model predictions and experimental data from batch fermentation of cellobiose, xylose and their mixtures. Additionally, with the guidance of model prediction, simultaneous co-fermentation of 60 g/L cellobiose and 20 g/L xylose was achieved with the initial cell densities of 0.45 g dry cell weight /L for EJ2 and 0.9 g dry cell weight /L SR8. The results demonstrated that the kinetic modeling could be used to guide the design and optimization of yeast co-culture conditions for achieving simultaneous fermentation of cellobiose and xylose with improved ethanol productivity, which is critically important for robust and efficient renewable biofuel production from lignocellulosic biomass.

UV Resistance Locus 8 (UVR8), an ultraviolet-B (UV-B; 280-315 nm) photoreceptor, participates in the regulation of various plant growth and developmental processes. UV-B radiation is an important factor enhancing the production of active components in medicinal plants. To-date, however, studies on UV-B photoreceptors have largely focused on Arabidopsis, and the functions of UVR8 in medicinal plants are still largely unknown. In the present study, a homolog of Arabidopsis UVR8, CmUVR8, was isolated from Chrysanthemum morifolium Ramat, and its structure and function were analyzed in detail. Protein sequence analysis showed that CmUVR8 contained nine conserved regulators of chromosome condensation 1 repeats, seven conserved bladed propellers, one C27 region, three "GWRHT" motifs and several crucial amino acid residues (such as 14 Trps and 2 Args), similar to AtUVR8. 3-D structural analysis of CmUVR8 indicated that its structure was similar to AtUVR8. Heterologous expression of CmUVR8 could rescued the deficient phenotype of uvr8-6, a mutant of UVR8 in Arabidopsis, indicating the role of CmUVR8 in the regulation of hypocotyl elongation and HY5 gene expression under UV-B irradiation. Moreover, CmUVR8 regulates UV-B-induced expression of four flavonoids biosynthesis-related genes and the UV-B-induced accumulation of flavonoids. Furthermore, the interaction between CmUVR8 and CmCOP1 were confirmed using a yeast two-hybrid assay. These results indicated that CmUVR8 plays important roles in UV-B signal transduction and the UV-B-induced accumulation of flavonoids, as a counterpart of AtUVR8.

Endophytic fungi strains (n = 81) were isolated from the leaves, barks, and fruits of Camellia oleifera from Hunan province (China) to delineate their species composition and potential as biological control agents of C. oleifera anthracnose. The fungi were identified by morphological and phylogenetic analyses. Fungal colonization rates of the leaves, barks, and fruits were 58.02, 27.16, and 14.81%, respectively. The isolates were identified as 14 genera, belonging to two subdivisions, Deuteromycotina and Ascomycotina; 87.65% of all isolates belonged to Deuteromycotina. The dominant species, occurring with a high relative frequency, were Pestalotiopsis sp. (14.81%), Penicillium sp. (14.81%), and Fusarium sp. (12.35%). The Simpson's and Shannon's diversity indices revealed the highest species diversity in the leaves, followed by the barks and fruits. The similarity index for the leaves versus barks comparison was the highest, indicating that the number of endophytic fungal species shared by the leaves and barks was higher than barks and fruits or leaves and fruits. Based on the results of dual culture experiments, only five strains exhibited antifungal activity against C. oleifera anthracnose pathogen, with isolate ty-64 (Oidium sp.) generating the broadest inhibition zones. Our results indicate that the endophytes associated with C. oleifera could be employed as natural agents controlling C. oleifera anthracnose.

Obstructive sleep apnea hypopnea syndrome (OSAHS) in children is associated with multiple system morbidities. Cognitive dysfunction as a result of central nervous system complication has been reported in children with OSAHS. However, the underlying mechanisms are poorly understood. Endoplasmic reticulum stress (ERS)-related apoptosis plays an important role in various diseases of the central nervous system, but very little is known about the role of ERS in mediating pathophysiological reactions to cognitive dysfunction in OSAHS. Chronic intermittent hypoxia (CIH) exposures, modeling OSAHS, across 2 and 4weeks in growing rats made more reference memory errors, working memory errors and total memory errors in the 8-Arm radial maze task, increased significantly TUNEL positive cells, upregulated the unfolded protein response in the hippocampus and prefrontal cortex as evidenced by increased phosphorylation of PKR-like endoplasmic reticulum kinase, inositol-requiring enzyme l and some downstream products. A selective inhibitor of eukaryotic initiation factor-2a dephosphorylation, salubrinal, prevented C/EBP-homologous protein activation in the hippocampus and prefrontal cortex throughout hypoxia/reoxygenation exposure. Our findings suggest that ERS mediated cell apoptosis may be one of the underlying mechanisms of cognitive dysfunction in OSAHS children. Further, a specific ERS inhibitor Salubrinal should be tested for neuroprotection against CIH-induced injury.

SAMHD1, a dNTP triphosphohydrolase (dNTPase), has a key role in human innate immunity. It inhibits infection of blood cells by retroviruses, including HIV, and prevents the development of the autoinflammatory Aicardi-Goutières syndrome (AGS). The inactive apo-SAMHD1 interconverts between monomers and dimers, and in the presence of dGTP the protein assembles into catalytically active tetramers. Here, we present the crystal structure of the human tetrameric SAMHD1-dGTP complex. The structure reveals an elegant allosteric mechanism of activation through dGTP-induced tetramerization of two inactive dimers. Binding of dGTP to four allosteric sites promotes tetramerization and induces a conformational change in the substrate-binding pocket to yield the catalytically active enzyme. Structure-based biochemical and cell-based biological assays confirmed the proposed mechanism. The SAMHD1 tetramer structure provides the basis for a mechanistic understanding of its function in HIV restriction and the pathogenesis of AGS.