The ligation between ERMAP, galectin-9 and dectin-2 promotes Kupffer cell phagocytosis and antitumor immunity.

Kupffer cells, the liver tissue resident macrophages, are critical in the detection and clearance of cancer cells. However, the molecular mechanisms underlying their detection and phagocytosis of cancer cells are still unclear. Using in vivo genome-wide CRISPR-Cas9 knockout screening, we found that the cell-surface transmembrane protein ERMAP expressed on various cancer cells signaled to activate phagocytosis in Kupffer cells and to control of liver metastasis. ERMAP interacted with ß-galactoside binding lectin galectin-9 expressed on the surface of Kupffer cells in a manner dependent on glycosylation. Galectin-9 formed a bridging complex with ERMAP and the transmembrane receptor dectin-2, expressed on Kupffer cells, to induce the detection and phagocytosis of cancer cells by Kupffer cells. Patients with low expression of ERMAP on tumors had more liver metastases. Thus, our study identified the ERMAP-galectin-9-dectin-2 axis as an 'eat me' signal for Kupffer cells.

METTL16 promotes hepatocellular carcinoma progression through downregulating RAB11B-AS1 in an m6A-dependent manner.

BACKGROUND: The molecular mechanisms driving hepatocellular carcinoma (HCC) remain largely unclear. As one of the major epitranscriptomic modifications, N6-methyladenosine (m6A) plays key roles in HCC. The aim of this study was to investigate the expression, roles, and mechanisms of action of the RNA methyltransferase methyltransferase-like protein 16 (METTL16) in HCC. METHODS: The expression of METTL16 and RAB11B-AS1 was determined by RT-qPCR. The regulation of RAB11B-AS1 by METTL16 was investigated by RNA immunoprecipitation (RIP), methylated RIP (MeRIP), and RNA stability assays. In vitro and in vivo gain- and loss-of-function assays were performed to investigate the roles of METTL16 and RAB11B-AS1. RESULTS: METTL16 was upregulated in HCC, and its increased expression was correlated with poor prognosis of HCC patients. METTL16 promoted HCC cellular proliferation, migration, and invasion, repressed HCC cellular apoptosis, and promoted HCC tumoral growth in vivo. METTL16 directly bound long noncoding RNA (lncRNA) RAB11B-AS1, induced m6A modification of RAB11B-AS1, and decreased the stability of RAB11B-AS1 transcript, leading to the downregulation of RAB11B-AS1. Conversely to METTL16, RAB11B-AS1 is downregulated in HCC, and its decreased expression was correlated with poor prognosis of patients with HCC. Furthermore, the expression of RAB11B-AS1 was negatively correlated with METTL16 in HCC tissues. RAB11B-AS1 repressed HCC cellular proliferation, migration, and invasion, promoted HCC cellular apoptosis, and inhibited HCC tumoral growth in vivo. Functional rescue assays revealed that overexpression of RAB11B-AS1 reversed the oncogenic roles of METTL16 in HCC. CONCLUSIONS: This study identified the METTL16/RAB11B-AS1 regulatory axis in HCC, which represented novel targets for HCC prognosis and treatment.

Associations of Face-to-Face and Instant Messaging Family Communication and Their Contents With Family Wellbeing and Personal Happiness Amidst the COVID-19 Pandemic.

Background: Both face-to-face and instant messaging (IM) communication are important for families, but face-to-face communication has reduced amidst the COVID-19 pandemic. We examined the use and contents of both communication methods amidst the pandemic, their associations with family wellbeing and personal happiness, and the mediation effects of communication quality in Hong Kong Chinese adults. Methods: This population-based online survey enrolled 4,921 respondents in May 2020, who reported (i) any face-to-face or IM family communication when the pandemic was severe; (ii) communication contents being classified as neutral, positive, supportive, and negative; and (iii) communication quality, family wellbeing and personal happiness (score 0-10). Associations of family wellbeing and personal happiness with communication methods and contents (no communication excluded) were examined using linear regressions (ß), adjusting for each other, sex, age, socioeconomic status, and the number of cohabitants. Mediating effects of communication quality on these associations were examined. Prevalence estimates were weighted by sex, age, and education of the general population. Interactions of methods and contents were examined. Results: Of 4,891 included respondents (female: 52.9%, 45-54 years: 37.7%, ≥65 years: 21.3%), 7.1% reported no communication, 12.7% face-to-face communication only, 26.7% IM only, and 53.4% both methods. More males and those at younger ages, had lower socioeconomic status, or fewer cohabitants showed no family communication or face-to-face only. More respondents reported neutral (83.1-99.3%) than positive (42.1-62.2%), supportive (37.5-54.8%), and negative (10.9-34.5%) contents despite communication methods. Communication quality was higher with both methods than IM only, face-to-face only, and no communication (scores: 6.7 vs. 4.5-6.6, all P ≤ 0.02). Better family wellbeing and personal happiness were associated with using IM only (adjusted ßs: 0.37 and 0.48) and both methods (0.37 and 0.42) than face-to-face only, and positive (0.62 and 0.74) or supportive (0.45 and 0.46) contents (all P ≤ 0.001). Communication quality mediated 35.2-93.5% of these associations. Stronger associations between positive contents and family wellbeing showed in both methods and face-to-face only than IM only (P for interaction = 0.006). Conclusions: We have first shown that, amidst the COVID-19 pandemic, family IM communication and positive and supportive contents may promote family wellbeing and personal happiness. People with no family communication may need assistance.

Corrigendum: Associations of Delay in Doctor Consultation With COVID-19 Related Fear, Attention to Information, and Fact-Checking.

[This corrects the article DOI: 10.3389/fpubh.2021.797814.].

Characterization of antimicrobial resistance and virulence genes of Pseudomonas aeruginosa isolated from mink in China, 2011-2020.

Pseudomonas aeruginosa strains are potential pathogens that cause respiratory diseases in minks, and caused serious economic loss to mink breeding industry. In this study, we identified antimicrobial resistance and virulence genes in 125 P. aeruginosa isolates from mink in China from 2011 to 2020. The results showed at least one mutation in the gyrA (Thr83Val or Asp87Gly) and parC (Ser87 Leu) genes as well as single mutations in 56 isolates. At least 4-fold reductions in the fluoroquinolone minimum inhibitory concentration values were found when tested in the presence of PAßN in 23 isolates, while 44 isolates were positive for the extended spectrum ß-lactamases and 15 antibiotic resistance genes were identified in this population with a prevalence between 1-32%, including qnrA, CTX-M-1G, ermB and C, cmlA, flor, catl, intl1, tetA, B, C, and D as well as sul1, 2, and 3 genes. Interestingly, one isolate carried ten resistance genes. Five virulence genes were detected, where exoS and algD were the most frequently detected (76.8%), which were followed by plcH (76%), lasB (73.6%), and pilB (31.2%). The isolates carrying the antibiotic resistance or virulence genes were genetically variable, suggesting a horizontal spread through the population. Hence, this study provides novel and important data on the resistance and pathogenicity of P. aeruginosa in farmed mink infections. These data provide important insights into the mechanism of fluoroquinolone resistance in P. aeruginosa, highlighting its usefulness in the treatment and control of P. aeruginosa infections in minks.

High-frequency spinal cord stimulation produces long-lasting analgesic effects by restoring lysosomal function and autophagic flux in the spinal dorsal horn.

High-frequency spinal cord stimulation (HF-SCS) has been established as an effective therapy for neuropathic pain. However, the analgesic mechanisms involved in HF-SCS remain to be clarified. In our study, adult rat neuropathic pain was induced by spinal nerve ligation. Two days after modeling, the rats were subjected to 4 hours of HF-SCS (motor threshold 50%, frequency 10,000 Hz, and pulse width 0.024 ms) in the dorsal horn of the spinal cord. The results revealed that the tactile allodynia of spinal nerve-injured rats was markedly alleviated by HF-SCS, and the effects were sustained for 3 hours after the stimulation had ceased. HF-SCS restored lysosomal function, increased the levels of lysosome-associated membrane protein 2 (LAMP2) and the mature form of cathepsin D (matu-CTSD), and alleviated the abnormally elevated levels of microtubule-associated protein 1A/B-light chain 3 (LC3)-II and sequestosome 1 (P62) in spinal nerve-injured rats. HF-SCS also mostly restored the immunoreactivity of LAMP2, which was localized in neurons in the superficial layers of the spinal dorsal horn in spinal nerve-injured rats. In addition, intraperitoneal administration of 15 mg/kg chloroquine for 60 minutes reversed the expression of the aforementioned proteins and shortened the timing of the analgesic effects of HF-SCS. These findings suggest that HF-SCS may exhibit long-lasting analgesic effects on neuropathic pain in rats through improving lysosomal dysfunction and alleviating autophagic flux. This study was approved by the Laboratory Animal Ethics Committee of China Medical University, Shenyang, China (approval No. 2017PS196K) on March 1, 2017.

In vivo Pharmacokinetic/Pharmacodynamic (PK/PD) Profiles of Tulathromycin in an Experimental Intraperitoneal Haemophilus parasuis Infection Model in Neutropenic Guinea Pigs.

Tulathromycin is a semi-synthetic macrolide antimicrobial that has an important role in veterinary medicine for respiratory disease. The objective of the study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model to examine the efficacy and determine an optimal dosage of tulathromycin intramuscular (IM) treatment against Haemophilus parasuis infection induced after intraperitoneal inoculation in neutropenic guinea pigs. The PKs of tulathromycin in serum and lung tissue after intramuscular administration at doses of 1, 10, and 20 mg/kg in H. parasuis-infected neutropenic guinea pigs were evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The tulathromycin minimum inhibitory concentration (MIC) against H. parasuis was ~16 times lower in guinea pig serum (0.03 µg/mL) than in cation-adjusted Mueller-Hinton broth (CAMHB) (0.5 µg/mL). The ratio of the 168-h area under the concentration-time curve (AUC) to MIC (AUC168h/MIC) positively correlated with the in vivo antibacterial effectiveness of tulathromycin (R 2 = 0.9878 in serum and R 2 = 0.9911 in lung tissue). The computed doses to achieve a reduction of 2-log10 CFU/lung from the ratios of AUC72h/MIC were 5.7 mg/kg for serum and 2.5 mg/kg for lung tissue, which lower than the values of 13.2 mg/kg for serum and 8.9 mg/kg for lung tissue with AUC168h/MIC. In addition, using as objective a 2-log10 reduction and an AUC0-72h as the value of the PK/PD index could be more realistic. The results of this study could provide a solid foundation for the application of PK/PD models in research on macrolide antibiotics used to treat respiratory diseases.

Associations of Delay in Doctor Consultation With COVID-19 Related Fear, Attention to Information, and Fact-Checking.

Background: Delaying doctor consultation is harmful. Fear of COVID-19 leads to delays in seeking medical care at a time when pandemic information overflows. However, little is known about the role of COVID-19 related fear, attention to information, and fact-checking in such delay. Objective: Under the Hong Kong Jockey Club SMART Family-Link Project, we examined the associations of delay in doctor consultation amidst the pandemic with sociodemographic characteristics, COVID-19 related fear, attention to information, and fact-checking. Methods: We conducted a population-based online cross-sectional survey in May 2020 on Hong Kong Chinese adults. Respondents reported whether the pandemic caused any delay in doctor consultation (yes/no), level of COVID-19 related fear, attention to information and fact-checking (all on a scale of 0 to 10 and recoded into tertiles of low, moderate, high). Regression analyses were used to examine the associations of delay and fear with sociodemographic characteristics, attention and fact-checking, adjusting for covariates. Data were weighted by sex, age and education level of the population. Results: Of 4,551 respondents (46.5% male, 59.7% aged over 45 years), 10.1% reported delay in doctor consultation. The mean score was 6.4 for fear, 8.0 for attention and 7.4 for fact-checking. Delay was more common in males and increased with age and fear. High vs. low level of fear was associated with delay [adjusted odd ratios (AOR) 2.68, 95% confidence interval (CI) 2.08, 3.47]. Moderate level of fact-checking was negatively associated with delay (AOR 1.28, 95% CI 0.98, 1.67). Females reported greater fear and fear decreased with age. Fear increased with attention to information and decreased with fact-checking. Fear substantially mediated the association of delay with attention (96%) and fact-checking (30%). Conclusions: We have first shown that delay in doctor consultation increased with fear of COVID-19 and decreased with fact-checking amidst the pandemic. Fear also increased with attention to COVID-19 related information and decreased with fact-checking. Understanding these associations can help policymakers develop targeted communication and support to the public to reduce delayed doctor consultations and the associated COVID-19-related or unrelated morbidity and mortality in the community.

SLC38A4 functions as a tumour suppressor in hepatocellular carcinoma through modulating Wnt/ß-catenin/MYC/HMGCS2 axis.

BACKGROUND: Many molecular alterations are shared by embryonic liver development and hepatocellular carcinoma (HCC). Identifying the common molecular events would provide a novel prognostic biomarker and therapeutic target for HCC. METHODS: Expression levels and clinical relevancies of SLC38A4 and HMGCS2 were investigated by qRT-PCR, western blot, TCGA and GEO datasets. The biological roles of SLC38A4 were investigated by functional assays. The downstream signalling pathway of SLC38A4 was investigated by qRT-PCR, western blot, immunofluorescence, luciferase reporter assay, TCGA and GEO datasets. RESULTS: SLC38A4 silencing was identified as an oncofetal molecular event. DNA hypermethylation contributed to the downregulations of Slc38a4/SLC38A4 in the foetal liver and HCC. Low expression of SLC38A4 was associated with poor prognosis of HCC patients. Functional assays demonstrated that SLC38A4 depletion promoted HCC cellular proliferation, stemness and migration, and inhibited HCC cellular apoptosis in vitro, and further repressed HCC tumorigenesis in vivo. HMGCS2 was identified as a critical downstream target of SLC38A4. SLC38A4 increased HMGCS2 expression via upregulating AXIN1 and repressing Wnt/ß-catenin/MYC axis. Functional rescue assays showed that HMGCS2 overexpression reversed the oncogenic roles of SLC38A4 depletion in HCC. CONCLUSIONS: SLC38A4 downregulation was identified as a novel oncofetal event, and SLC38A4 was identified as a novel tumour suppressor in HCC.

Normal cells repel WWOX-negative or -dysfunctional cancer cells via WWOX cell surface epitope 286-299.

Metastatic cancer cells are frequently deficient in WWOX protein or express dysfunctional WWOX (designated WWOXd). Here, we determined that functional WWOX-expressing (WWOXf) cells migrate collectively and expel the individually migrating WWOXd cells. For return, WWOXd cells induces apoptosis of WWOXf cells from a remote distance. Survival of WWOXd from the cell-to-cell encounter is due to activation of the survival IκBα/ERK/WWOX signaling. Mechanistically, cell surface epitope WWOX286-299 (repl) in WWOXf repels the invading WWOXd to undergo retrograde migration. However, when epitope WWOX7-21 (gre) is exposed, WWOXf greets WWOXd to migrate forward for merge. WWOX binds membrane type II TGFß receptor (TßRII), and TßRII IgG-pretreated WWOXf greet WWOXd to migrate forward and merge with each other. In contrast, TßRII IgG-pretreated WWOXd loses recognition by WWOXf, and WWOXf mediates apoptosis of WWOXd. The observatons suggest that normal cells can be activated to attack metastatic cancer cells. WWOXd cells are less efficient in generating Ca2+ influx and undergo non-apoptotic explosion in response to UV irradiation in room temperature. WWOXf cells exhibit bubbling cell death and Ca2+ influx effectively caused by UV or apoptotic stress. Together, membrane WWOX/TßRII complex is needed for cell-to-cell recognition, maintaining the efficacy of Ca2+ influx, and control of cell invasiveness.

Induced defense and its cost in two bryophyte species.

PREMISE: Current knowledge about defense strategies in plants under herbivore pressure is predominantly based on vascular plants. Bryophytes are rarely consumed by herbivores since they have ample secondary metabolites. However, it is unknown whether bryophytes have induced defenses against herbivory and whether there is a trade-off between growth and defense in bryophytes. METHODS: In an experiment with two peatland bryophytes, Sphagnum magellanicum Brid. and S. fuscum (Schimp.) H. Klinggr., two kinds of herbivory, clipping with scissors and grazing by mealworms (Tenebrio molitor L.) were simulated. At the end of the experiment, we measured growth traits, carbon-based defense compounds (total phenolics and cellulose) and storage compounds (total nonstructural carbohydrates) of these two Sphagnum species. RESULTS: Grazing but not clipping increased total phenolics and C:N ratio and reduced biomass production and height increment. A negative relationship between biomass production and total phenolics was found in S. magellanicum but not in S. fuscum, indicating a growth-defense trade-off that is species-specific. Grazing reduced the sugar starch content of S. magellanicum and the sugar of S. fuscum. Either clipping or grazing had no effect on chlorophyll fluorescence (including actual and maximum photochemical efficiency of photosystem II) except that a significant effect of clipping on actual photochemical efficiency in S. fuscum was observed. CONCLUSIONS: Our results suggest that Sphagnum can have induced defense against herbivory and that this defense can come at a cost of growth. These findings advance our knowledge about induced defense in bryophytes, the earliest land plants.

Inhibition or Facilitation? Contrasted Inter-Specific Interactions in Sphagnum under Laboratory and Field Conditions.

In a natural environment, plants usually interact with their neighbors predominantly through resource competition, allelopathy, and facilitation. The occurrence of the positive effect of allelopathy between peat mosses (Sphagnum L.) is rare, but it has been observed in a field experiment. It is unclear whether the stability of the water table level in peat induces positive vs. negative effects of allelopathy and how that is related to phenolic allelochemical production in Sphagnum. Based on field experiment data, we established a laboratory experiment with three neighborhood treatments to measure inter-specific interactions between Sphagnum angustifolium (Russ.) C. Jens and Sphagnum magellanicum Brid. We found that the two species were strongly suppressed by the allelopathic effects of each other. S. magellanicum allelopathically facilitated S. angustifolium in the field but inhibited it in the laboratory, and relative allelopathy intensity appeared to be positively related to the content of released phenolics. We conclude that the interaction type and intensity between plants are dependent on environmental conditions. The concentration of phenolics alone may not explain the type and relative intensity of allelopathy. Carefully designed combined field and laboratory experiments are necessary to reveal the mechanism of species interactions in natural communities.

Cancer-testis Antigen OY-TES-1 Expression and Immunogenicity in Hepatocellular Carcinoma.

Cancer testis (CT) antigens have received particular attention in cancer immunotherapy. OY-TES-1 is a member of CT antigens. This study was to evaluate OY-TES-1 expression and immunogenicity in hepatocelluar carcinoma (HCC). OY-TES-1 mRNA expression was detected in 56 HCC tissues and 5 normal liver tissues by reverse transcriptase PCR (RT-PCR). Of the 56 cases of HCC tissues tested, 37 cases had tumor and matched adjacent non-cancer tissues and were subjected to both RT-PCR and quantitative real-time PCR. OY-TES-1 protein was subsequently observed on a panel of tissue microarrays. Sera from patients were tested for OY-TES-1 antibody by ELISA. To identify OY-TES-1 capable of inducing cellular immune response, OY-TES-1 protein was used to sensitize dentritic cells and the cytotoxicity effect was measured in vitro. The results showed that OY-TES-1 mRNA was highly expressed in 41 of the 56 (73.21%) HCC tissues, whereas none in 5 normal liver tissues. OY-TES-1 mRNA was frequently expressed not only in HCC tissues (72.97%, 27/37), but also in paired adjacent non-cancer tissues (64.86%, 24/37). But the mean expression level of OY-TES-1 mRNA in HCC tissues was significantly higher than that in adjacent non-cancer tissues (0.76854 vs. 0.09834, P=0.021). Immunohistochemistry showed that OY-TES-1 protein expression was detected in 6 of the 49 cases of HCC tissues, and absent in 9 cases of normal liver and 6 cases of cirrhosis tissues. Seropositivity was detected in 10 of the 45 HCC patients, but not detected in 17 cirrhosis patients and 76 healthy donors. The specific cytotoxic T cells elicited by OY-TES-1 could kill HLA-A2+ HCC cell line which expressed OY-TES-1. The target lysis was mainly HLA class I -dependent and could be blocked by antibodies against monomorphic HLA class I but not HLA class II molecule. In summary, OY-TES-1 expression is up-regulated in HCC tissues and can be recognized by humoral and cellular responses, which suggests that OY-TES-1 is an attractive target for tumor immunotherapy in HCC.

Evodiamine has therapeutic efficacy in ulcerative colitis by increasing Lactobacillus acidophilus levels and acetate production.

Emerging evidence implicates gut microbiota have an important role in ulcerative colitis (UC). Previous study indicated that Evodiamine (EVO) can alleviate colitis through downregulating inflammatory pathways. However, specific relationship between EVO-treated colitis relief and regulation of gut microbiota is still unclear. Here, our goal was to determine the potential role of gut microbiota in the relief of UC by EVO. By using pathology-related indicators, 16S rRNA sequencing and metabolomics profiling, we assessed the pharmacological effect of EVO on dextran sulfate sodium (DSS)-induced colitis rats as well as on the change of gut microbiota and metabolism. Fecal derived from EVO-treated rats was transplanted into colitis rats to verify the effect of EVO on gut microbiota, and 'driver bacteria' was found and validated by 16S rRNA sequencing, metagenome and qRT-PCR. The effect of Lactobacillus acidophilus (L. acidophilus) was investigated by vivo experiment, microbiota analysis, Short-chain fatty acids (SCFAs) quantification and colon transcriptomics. EVO reduced the susceptibility to DSS-induced destruction of epithelial integrity and severe inflammatory response, and regulated the gut microbiota and metabolites. Fecal Microbiota Transplantation (FMT) alleviated DSS-induced colitis, increased the abundance of L. acidophilus and the level of acetate. Furthermore, gavaged with L. acidophilus reduced pro-inflammatory cytokines, promoted the increase of goblet cells and the secretion of antimicrobial peptides, regulated the ratio of Firmicutes/Bacteroidetes and increased the level of acetate. Our results indicated that EVO mitigation of DSS-induced colitis is associated with increased in L. acidophilus and protective acetate production, which may be a promising strategy for treating UC.

Strategies by which WWOX-deficient metastatic cancer cells utilize to survive via dodging, compromising, and causing damage to WWOX-positive normal microenvironment.

Proapoptotic tumor suppressor WWOX is upregulated in the early stage of cancer initiation, which probably provides limitation to cancer growth and progression. Later, WWOX protein is reduced to enhance cancer cell growth, migration, invasiveness and metastasis. To understand how WWOX works in controlling cancer progression, here we demonstrate that apoptotic stress mediated by ectopic WWOX stimulated cancer cells to secrete basic fibroblast growth factor (bFGF) in order to support capillary microtubule formation. This event may occur in the cancer initiation stage. Later, when WWOX loss occurs in cancer cells, hyaluronidase production is then increased in the cancer cells to facilitate metastasis. We determined that inhibition of membrane hyaluronidase Tyr216-phosphorylated Hyal-2 by antibody suppresses cancer growth in vivo. WWOX-negative (WWOX-) cells dodged WWOX+cells in the microenvironment by migrating individually backward to avoid physical contacts and yet significantly upregulating the redox activity of WWOX+parental cells or other WWOX+cell types for causing apoptosis. Upon detecting the presence of WWOX+cells from a distance, WWOX- cells exhibit activation of MIF, Hyal-2, Eph, and Wnt pathways, which converges to MEK/ERK signaling and enables WWOX- cells to evade WWOX+cells. Inhibition of each pathway by antibody or specific chemicals enables WWOX- cells to merge with WWOX+cells. In addition, exogenous TGF-ß assists WWOX- cells to migrate collectively forward and merge with WWOX+cells. Metastatic WWOX- cancer cells frequently secrete high levels of TGF-ß, which conceivably assists them to merge with WWOX+cells in target organs and secure a new home base in the WWOX+microenvironment. Together, loss of WWOX allows cancer cells to develop strategies to dodge, compromise and even kill WWOX-positive cells in microenvironment.

Systematic analysis of alternative splicing signature unveils prognostic predictor for kidney renal clear cell carcinoma.

There is growing evidence that alternative splicing (AS) plays an important role in cancer development. However, a comprehensive analysis of AS signatures in kidney renal clear cell carcinoma (KIRC) is lacking and urgently needed. It remains unclear whether AS acts as diagnostic biomarkers in predicting the prognosis of KIRC patients. In the work, gene expression and clinical data of KIRC were obtained from The Cancer Genome Atlas (TCGA), and profiles of AS events were downloaded from the SpliceSeq database. The RNA sequence/AS data and clinical information were integrated, and we conducted the Cox regression analysis to screen survival-related AS events and messenger RNAs (mRNAs). Correlation between prognostic AS events and gene expression were analyzed using the Pearson correlation coefficient. Protein-protein interaction analysis was conducted for the prognostic AS-related genes, and a potential regulatory network was built using Cytoscape (version 3.6.1). Meanwhile, functional enrichment analysis was conducted. A prognostic risk score model is then established based on seven hub genes (KRT222, LENG8, APOB, SLC3A1, SCD5, AQP1, and ADRA1A) that have high performance in the risk classification of KIRC patients. A total 46,415 AS events including 10,601 genes in 537 patients with KIRC were identified. In univariate Cox regression analysis, 13,362 survival associated AS events and 8,694 survival-specific mRNAs were detected. Common 3,105 genes were screen by overlapping 13,362 survival associated AS events and 8,694 survival-specific mRNAs. The Pearson correlation analysis suggested that 13 genes were significantly correlated with AS events (Pearson correlation coefficient >0.8 or <-0.8). Then, We conducted multivariate Cox regression analyses to select the potential prognostic AS genes. Seven genes were identified to be significantly related to OS. A prognostic model based on seven genes was constructed. The area under the ROC curve was 0.767. In the current study, a robust prognostic prediction model was constructed for KIRC patients, and the findings revealed that the AS events could act as potential prognostic biomarkers for KIRC.

Nine-sector three-stage Fresnel lens concentrator: publisher's note.

This publisher's note amends the author listing in Appl. Opt.58, 122 (2019)APOPAI0003-693510.1364/AO.58.000122.

Hyperbaric oxygen relieves neuropathic pain through AKT/TSC2/mTOR pathway activity to induce autophagy.

BACKGROUND: Our previous study suggested that HBO treatment attenuated neuropathic pain by inhibiting mTOR to induce autophagy in SNL neuropathic pain model. The aim of this study was to evaluate the role of AKT/TSC2/mTOR pathway in SNL and autophagy and determine whether HBO treatment could relieve neuropathic pain via modulating AKT/TSC2/mTOR pathway. MATERIALS AND METHODS: Rats were randomly divided into sham, SNL, SNL + HBO treatment, SNL + vehicle, and SNL + AKT inhibitor groups. Neuropathic pain was induced following SNL procedure. Rats in the SNL + HBO group received HBO treatment for 7 consecutive days beginning on postoperative day 1. The SNL + vehicle group received 10 µL of 3% dimethyl sulfoxide in saline. SNL + AKT inhibitor group received 10 µL AKT inhibitor IV intrathecally. Mechanical withdrawal threshold tests were performed to evaluate mechanical hypersensitivity. AKT, p-AKT, TSC2, mTOR, p-mTOR, and LC3-II protein expressions were examined by Western blot analysis. RESULTS: HBO reversed AKT/TSC2/mTOR upregulation induced by SNL and attenuated neuropathic pain. Intrathecal injection of AKT inhibitor IV decreased the activity of AKT/TSC2/mTOR pathway and increased LC3-II expression accompanied by analgesic effect in SNL rats. CONCLUSION: Taken together, our findings demonstrated AKT/TSC2/mTOR pathway was activated in SNL-induced neuropathic pain, and HBO treatment attenuated neuropathic pain via neutralizing AKT/TSC2/mTOR pathway activation.

Nine-sector three-stage Fresnel lens concentrator.

In this paper, we design a three-stage Fresnel lens concentrator with a low f number. The proposed concentrator consists of a primary optical element (POE) and a second optical element (SOE). The nine-sector three-stage Fresnel lens is composed of three types of triangular prisms: the refractive triangular prism, single total internal reflection triangular prism, and double total internal reflection triangular prism. In order to increase the uniformity and acceptance angle of the POE coupled to the SOE, the SOE is also divided into nine sectors. Finally, it is found that this nine-sector three-stage Fresnel lens concentrator can achieve a concentration ratio of 1000×; the uniformity is 25.8, optical efficiency is 81.8%, f number is 0.46, and acceptance angle is ±0.73°.

A novel experimental intraperitoneal infection model for Haemophilus parasuis in neutropenic guinea pigs.

INTRODUCTION: Haemophilus parasuis, one of the major swine pathogens, has at least fifteen different types, all of which have significant economic effects on the global swine industry. The aim of this study was to establish an experimental intraperitoneal infection model for H. parasuis in neutropenic guinea pigs. METHODS: Intraperitoneal administration of cyclophosphamide and Haemophilus parasuis was conducted in guinea pigs. Clinical signs, gross pathology, and histopathology were observed in neutropenic guinea pigs infected with H. parasuis. RESULTS: Intraperitoneal administration of 100 mg/kg cyclophosphamide led to immunosuppression with white blood cells, lymphocytes, and neutrophils all <1000 mm3, while no histological tissue damage was observed. Intraperitoneal administration of 109 colony-forming units (CFU) of H. parasuis led to typical respiratory symptoms, 90% morbidity, and 20% mortality in a 72 h-period. Bacteriological screening revealed that multiple organs, including the heart, liver, spleen, lungs, kidneys, and blood, were infected with H. parasuis. The threshold loads of bacteria in blood and the lungs were (7.04 ±â€¯0.53)log10 CFU/mL and (6.24 ±â€¯0.62)log10 CFU/g, respectively, at 3 d after infection. Gross pathology examination showed celiac effusion, intestinal mucosal hemorrhage, and liver, spleen, or lung swelling, necrosis, and hemorrhage. Congestion, mild interstitial pneumonia, inflammatory exudation, and endothelial cell proliferation were observed in the histological examination. DISCUSSION: All the results suggest that we have established an experimental intraperitoneal infection model for H. parasuis in neutropenic guinea pigs. It is especially useful as a tool for pharmacokinetics, pharmacodynamics, or a pharmacokinetics/pharmacodynamics (PK/PD) model of antimicrobial agents against respiratory disease.