Development of a recombinant adenovirus-vectored vaccine against both infectious hematopoietic necrosis virus and infectious pancreatic necrosis virus in rainbow trout (Oncorhynchus mykiss).

Infectious hematopoietic necrosis virus (IHNV) and infectious pancreatic necrosis virus (IPNV) are typical pathogens of rainbow trout Oncorhynchus mykiss, and the concurrent infection of the two viruses is very common among modern trout hatcheries, which has caused huge economic losses to the rainbow trout farming industry. To prevent and control the spread of IHNV and IPNV in juvenile trout simultaneously, in this study a bivalent recombinant adenovirus vaccine with IHNV Glycoprotein (G) and IPNV VP2 genes was developed. After immunizing juvenile trout with this bivalent vaccine via the immersion route, the expression levels of IHNV G and IPNV VP2 and the representative immune genes in vaccinated and control rainbow trout were tested to evaluate the correlation of immune responses with the expression of viral genes. The neutralizing antibody level induced by this bivalent vaccine as well as the protection efficacy of the vaccine against IHNV and IPNV was also evaluated. The results showed that IHNV G and IPNV VP2 were successfully expressed in juvenile trout, and all the innate and adaptive immune genes were up-regulated. This indicated that the level of the innate and adaptive immune responses were significantly increased, which might be induced by the high expression of the two viral proteins. Compared with the controls, high levels of neutralizing antibodies against IHNV and IPNV were induced in the vaccinated trout. Besides, the bivalent recombinant adenovirus vaccine showed high protection rate against IHNV, with the relative percent survival (RPS) of 81.25%, as well as against IPNV, with the RPS of 78.95%. Taken together, our findings clearly demonstrated that replication-defective adenovirus can be developed as a qualified vector for fish vaccines and IHNV G and IPNV VP2 were two suitable antigenic genes that could induce effective immune protection against these two pathogens. This study provided new insights into developing bivalent vectored vaccines and controlling the spread of IHNV and IPNV simultaneously in juvenile trout.

A novel C-type lectin (SpccCTL) suppresses MCRV replication by binding viral protein and regulating antiviral peptides in Scylla paramamosain.

Pattern recognition receptors (PRRs) play a crucial role in the recognition and activation of innate immune responses against invading microorganisms. This study characterizes a novel C-type lectin (CTL), SpccCTL. The cDNA sequence of SpccCTL has a full length of 1744 bp encoding a 338-amino acid protein. The predicted protein contains a signal peptide, a coiled-coil (CC) domain, and a CLECT domain. It shares more than 50 % similarity with a few CTLs with a CC domain in crustaceans. SpccCTL is highly expressed in gills and hemocytes and upregulated after MCRV challenge, suggesting that it may be involved in antiviral immunity. Recombinant SpccCTL (rSpccCTL) as well as two capsid proteins of MCRV (VP11 and VP12) were prepared. Pre-incubating MCRV virions with rSpccCTL significantly suppresses the proliferation of MCRV in mud crabs, compared with the control (treatment with GST protein), and the survival rate of mud crabs is also significantly decreased. Knockdown of SpccCTL significantly facilitates the proliferation of MCRV in mud crabs. These results reveal that SpccCTL plays an important role in antiviral immune response. GST pull-down assay result shows that rSpccCTL interacts specifically with VP11, but not to VP12. This result is further confirmed by a Co-IP assay. In addition, we found that silencing SpccCTL significantly inhibits the expression of four antimicrobial peptides (AMPs). Considering that these AMPs are members of anti-lipopolysaccharide factor family with potential antiviral activity, they are likely involved in immune defense against MCRV. Taken together, these findings clearly demonstrate that SpccCTL can recognize MCRV by binding viral capsid protein VP11 and regulate the expression of certain AMPs, suggesting that SpccCTL may function as a potential PRR playing an essential role in anti-MCRV immunity of mud crab. This study provides new insights into the antiviral immunity of crustaceans and the multifunctional characteristics of CTLs.

Phagocytosis-Regulators-Based Signature to Predict the Prognosis and Chemotherapy Resistance for Breast Cancer Patients.

Phagocytosis is crucial in tumor surveillance and immune function. The association between phagocytosis and the outcomes of breast cancer patients has not been well-determined. In this study, data were downloaded from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases to investigate the role of phagocytosis in breast cancer. Data from the TCGA and GEO databases were used to investigate the prognostic role of phagocytosis in breast cancer. Then, we performed pathway enrichment analysis, copy number variation (CNV) and single-nucleotide variant (SNV) analyses, immune infiltration analysis, calculation of tumor purity, stromal score, and immune score, and consistent clustering. We also constructed a phagocytosis-regulators-based signature system to examine its association in survival and drug response. The genomic and expression differences in the phagocytosis regulators in breast cancer were systematically analyzed, explaining the widespread dysregulation of phagocytosis regulators. Using the investigated association of phagocytosis regulators with the prognosis and tumor immune environment, we constructed a prognostic model based on phagocytosis regulators. We discovered that patients with high risk scores had a poor prognosis and were negatively associated with immune functions. The model had preferential predictive performance and significantly consistent drug-resistance prediction results. Our findings suggest that the phagocytosis-factors-based scoring system can be used as a novel prognostic factor, serving as a powerful reference tool for predicting prognosis and developing methods against drug resistance.

Na-Ln Heterometallic Coordination Polymers: Structure Modulation by Na+ Concentration and Efficient Detection to Tetracycline Antibiotics and 4-(Phenylazo)aniline.

On the basis of the lanthanide metalloligand [Ln(ODA)3]3- (H2ODA = oxydiacetic acid), three new Na-Ln heterometallic coordination polymers, [Ln(ODA)3Na2]n [Ln = Eu (1) and Gd (2)] and [Tb(ODA)3Na3(H2O)2]n (3), had been assembled by adjusting the concentration of Na+ ions in the reaction system. The investigations of fluorescence sensing showed that 1 could be a ratiometric probe to detect tetracycline (TC) and oxytetracycline (OTC) with high sensitivity and low detection limits, 71.92 ppb for the former and 45.54 ppb for the latter, and 3 could selectively sense 4-(phenylazo)aniline through the turn-off pathway with 14.59 ppb of detection limits. Moreover, the competing and circulating experiments indicated that both 1 and 3 had satisfactory antiinterference and recyclability for the corresponding analytes. All of these results implied that 1 and 3 should be potential fluorescent sensors for the detection of TC/OTC and 4-(phenylazo)aniline, and the possible sensing mechanism had also been discussed in depth.

Metabolic gene signature for predicting breast cancer recurrence using transcriptome analysis.

Background: The study aimed at identifying a metabolic gene signature for stratifying the risk of recurrence in breast cancer. Materials & methods: The data of patients were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The limma package was used to identify differentially expressed metabolic genes, and a metabolic gene signature was constructed. Results: A five-gene metabolic signature was established that demonstrated satisfactory accuracy and predictive power in both training and validation cohorts. Also, a nomogram for predicting recurrence-free survival was established using a combination of the metabolism gene risk score and the clinicopathological features. Conclusions: The proposed metabolic gene signature and nomogram have a significant prognostic value and may improve the recurrence risk stratification for breast cancer patients.

TMT-based proteomic analysis of the fish-borne spoiler Pseudomonas psychrophila subjected to chitosan oligosaccharides in fish juice system.

P. psychrophila is implicated in fish spoilage especially under cold storage. In the present study, tandem mass tag (TMT) quantitative proteomic analysis was performed to clarify the molecular mechanism for the inhibitory effect of chitosan oligosaccharides (COS) against P. psychrophila in fish juice system. The MIC and MBC of the COS against P. psychrophila were 6 and 8 mg/mL, respectively. Compared with the untreated control, a total of 370 proteins (163 up-regulated and 207 down-regulated) were identified as differentially expressed proteins (DEPs, >1.5-fold or < 0.67-fold, P < 0.05) in P. psychrophila when exposed to 6 mg/mL COS. Bioinformatics analysis indicated that the DEPs were mainly involved in the cell wall/membrane, cell motility, and electron-transport chain; DNA replication, RNA transcription and translation, posttranslational modifications of proteins; TCA cycle, and the transport and metabolism of amino acid, carbohydrate, and ion. The scanning electron microscope (SEM) and fourier-transform infrared spectroscopy (FT-IR) analysis further validated that cell structure especially the cell wall/membrane was damaged after COS treatment. The results in this study presented an important step toward understanding the response of P. psychrophila cells to COS at the proteome level.

Natural Sugar: A Green Assistance To Efficiently Exfoliate Inorganic Layered Nanomaterials.

We have demonstrated that natural sugars can efficiently exfoliate inorganic layered nanomaterials with direct stirring. The representative transition-metal dichalcogenides (MoS2 and WS2), transition-metal oxide (MoO3), and graphene were explored, and the formation of ultrathin nanosheets was verified. Glucose and MoS2 selected each other as the perfect partner with superior exfoliation and excellent properties. The obtained inorganic layered nanosheets possess favorable stability and dispersity, which renders it suitable for direct homogeneous liquid applications, such as catalytic activities and sensors. With a high-throughput and green process, the sugar-assisted method may offer new ideas for inorganic layered nanomaterials synthesis and applications in a more ecofriendly way.

Layered vanadium(IV) disulfide nanosheets as a peroxidase-like nanozyme for colorimetric detection of glucose.

The authors have discovered that vanadium disulfide (VS2) nanosheets, synthesized by a hydrothermal method, exert stable peroxidase-like activity. The catalytic activity, with H2O2 as a cosubstrate, follows Michaelis-Menten kinetics and varies with temperature, pH value and H2O2 concentration. Two-dimensional VS2 sheets acting as peroxidase (POx) mimics can replace horseradish peroxidase due to their availability, robustness, and reusability. The POx-like activity of VS2 sheets was exploited to design a colorimetric glucose assay by using 3,3',5,5'-tetramethylbenzidine as a substrate and by working at an analytical wavelength of 652 nm. The assay covers the 5 to 250 µM glucose concentration range with a 1.5 µM detection limit. It was applied to the analysis of glucose in fruit juice. In our perception, the peroxidase-like nanozyme out of the family of transition metal dichalcogenides presented here has a wide scope in that it may stimulate promising biocatalytic applications in biotechnology and analytical chemistry. Graphical abstract Layered VS2 nanosheets were prepared via hydrothermal synthesis and are shown to exert superior peroxidase-mimicking activity. Using these POx nano-mimics, a sensitive colorimetric assay for glucose was developed and applied to fruit juice analysis. This work unlocks the access of VS2 to biocatalysis and bioassays.

CFTR Controls the Activity of NF-κB by Enhancing the Degradation of TRADD.

BACKGROUND/AIMS: Chronic lung infection in cystic fibrosis leads to an inflammatory response that persists because of the chronic presence of bacteria and ultimately leads to a catastrophic failure of lung function. METHODS: We use a combination of biochemistry, cell and molecular biology to study the interaction of TRADD, a key adaptor molecule in TNFα signaling, with CFTR in the regulation of NFκB. RESULTS: We show that Wt CFTR binds to and colocalizes with TRADD. TRADD is a key signaling intermediate connecting TNFα with activation of NFκB. By contrast, ΔF508 CFTR does not bind to TRADD. NF-κB activation is higher in CFBE expressing ΔF508 CFTR than in cells expressing Wt CFTR. However, this differential effect is abolished when TRADD levels are knocked down. Transfecting Wt CFTR into CFBE cells reduces NF-κB activity. However the reduction is abolished by the CFTR chloride transport inhibitor-172. Consistently, transfecting in the correctly trafficked CFTR conduction mutants G551D or S341A also fail to reduce NFκB activity. Thus CFTR must be functional if it is to regulate NF-κB activity. We also found that TNFα produced a greater increase in NF-κB activity in CFBE cells than in the same cell when Wt CFTR-corrected. Consistently, the effect is also abolished when TRADD is knocked down by shRNA. Thus, Wt CFTR control of TRADD modulates the physiological activation of NF-κB by TNFα. Based on studies with proteosomal and lysosomal inhibitors, the mechanism by which Wt CFTR, but not ΔF508 CFTR, suppresses TRADD is by lysosomal degradation. CONCLUSION: We have uncovered a novel mechanism whereby Wt CFTR regulates TNFα signaling by enhancing TRADD degradation. Thus by reducing the levels of TRADD, Wt CFTR suppresses downstream proinflammatory NFκB signaling. By contrast, suppression of NF-κB activation fails in CF cells expressing ΔF508 CFTR.

Energy recovery from thermal treatment of dewatered sludge in wastewater treatment plants.

Sewage sludge is a by-product generated from municipal wastewater treatment (WWT) processes. This study examines the conversion of sludge via energy recovery from gasification/combustion for thermal treatment of dewatered sludge. The present analysis is based on a chemical equilibrium model of thermal conversion of previously dewatered sludge with moisture content of 60-80%. Prior to combustion/gasification, sludge is dried to a moisture content of 25-55% by two processes: (1) heat recovered from syngas/flue gas cooling and (2) heat recovered from syngas combustion. The electricity recovered from the combined heat and power process can be reused in syngas cleaning and in the WWT plant. Gas temperature, total heat and electricity recoverable are evaluated using the model. Results show that generation of electricity from dewatered sludge with low moisture content (≤ 70%) is feasible within a self-sufficient sludge treatment process. Optimal conditions for gasification correspond to an equivalence ratio of 2.3 and dried sludge moisture content of 25%. Net electricity generated from syngas combustion can account for 0.071 kWh/m(3) of wastewater treated, which is up to 25.4-28.4% of the WWT plant's total energy consumption.

Activation of 3-phosphoinositide-dependent kinase 1 (PDK1) and serum- and glucocorticoid-induced protein kinase 1 (SGK1) by short-chain sphingolipid C4-ceramide rescues the trafficking defect of ΔF508-cystic fibrosis transmembrane conductance regulator (ΔF508-CFTR).

Cystic fibrosis (CF) is due to a folding defect in the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, ΔF508, prevents CFTR from trafficking to the apical plasma membrane. Here we show that activation of the PDK1/SGK1 signaling pathway with C4-ceramide (C4-CER), a non-toxic small molecule, functionally corrects the trafficking defect in both cultured CF cells and primary epithelial cell explants from CF patients. The mechanism of C4-CER action involves a series of mutual autophosphorylation and phosphorylation events between PDK1 and SGK1. Detailed mechanistic studies indicate that C4-CER initially induces autophosphorylation of SGK1 at Ser(422). SGK1[Ser(P)(422)] and C4-CER coincidently bind PDK1 and permit PDK1 to autophosphorylate at Ser(241). Then PDK1[Ser(P)(241)] phosphorylates SGK1[Ser(P)(422)] at Thr(256) to generate fully activated SGK1[Ser(422), Thr(P)(256)]. SGK1[Ser(P)(422),Thr(P)(256)] phosphorylates and inactivates the E3 ubiquitin ligase Nedd4-2. ΔF508-CFTR is thus free to traffic to the plasma membrane. Importantly, C4-CER-mediated activation of both PDK1 and SGK1 is independent of the PI3K/Akt/mammalian target of rapamycin signaling pathway. Physiologically, C4-CER significantly increases maturation and stability of ΔF508-CFTR (t½ ∼10 h), enhances cAMP-activated chloride secretion, and suppresses hypersecretion of interleukin-8 (IL-8). We suggest that candidate drugs for CF directed against the PDK1/SGK1 signaling pathway, such as C4-CER, provide a novel therapeutic strategy for a life-limiting disorder that affects one child, on average, each day.

[Correlation of Twist and YB-1 up-regulation and epithelial-mesenchymal transition during tumorigenesis and progression of cervical carcinoma].

OBJECTIVE: To investigate the clinicopathological significance of Twist and YB-1 up-regulation in cervical cancer, and to correlate the expression of the two genes with E-cadherin, a marker of epithelial-mesenchymal transition (EMT). METHODS: A total of 202 tissue samples were collected during January 2008 to December 2013, including 50 cases of normal cervical tissues, 100 cases of cervical intraepithelial neoplasia (CIN) and 52 cases of squamous cell carcinoma (SCC). Twist, YB-1 and E-cadherin expression was investigated by MaxVision. RESULTS: Increased expression levels of Twist and YB-1 were found and correlated with the malignant transformation of cervical epithelium, histological progression and metastasis of cervical cancer. In addition, Twist and YB-1 overexpression was also associated with aberrant expression of E-cadherin. Regression analysis revealed that Twist expression was an independent factor for the histological progression of cervical cancer. CONCLUSIONS: It is suggested that Twist and YB-1 overexpression is significantly linked to cervical cancer tumorigenesis and progression, likely related to EMT through (YB-1)-Twist-(E-cadherin) pathway. Twist and YB-1 may be markers for determining the metastatic potential of cervical cancer.

Overexpression of SPP1 is a prognostic indicator of immune infiltration in lung adenocarcinoma.

OBJECTIVE: The extracellular phosphoprotein, secreted phosphoprotein 1 (SPP1), plays a crucial role in various tumors and regulating the immune system. This study aimed to evaluate its prognostic value and relationship to immune infiltration in lung adenocarcinoma (LUAD). METHODS: In the TCGA and GEO datasets, the information on clinic and transcriptome analysis of SPP1 in non-small-cell lung cancer (NSCLC) was examined accordingly. The association of SPP1 expression with overall survival and clinicopathologic characteristics was investigated by univariate and multivariate analysis. CancerSEA database was utilized to investigate the role of SPP1 at the cellular level by single-cell analysis. Additionally, the CIBERSORT algorithm was utilized to assess the correlation among the immune cells that infiltrated. RESULTS: NSCLC tissues exhibited a notable rise in SPP1 expression compared with that of normal tissues. Furthermore, the overexpression of SPP1 was substantially associated with clinicopathological features and unfavorable survival outcomes in individuals with LUAD, whereas no such correlation was observed in lung squamous cell carcinoma. Immune cells that infiltrate tumors and their corresponding genes were associated with SPP1 expression levels in LUAD. CONCLUSIONS: SPP1 is a reliable indicator for assessing LUAD immune infiltration status and prognosis. With this approach, SPP1 can help earlier LUAD diagnosis and act as a possible immunotherapy target.

How to survive the long night? Longitudinal relationship between sleep problems and suicidal behavior among adolescents: The serial mediating roles of negative emotion, self-control, and nonsuicidal self-injury.

OBJECTIVE: Sleep problems are a significant risk factor for identifying and preventing suicidal involvement among adolescents. However, there is limited evidence to assess the underlying mechanisms between them. This study investigated the longitudinal relationship between sleep problems and suicidal behavior and examined whether this relationship was moderated by negative emotions, low self-control, and nonsuicidal self-injury (NSSI). METHODS: From December 2020 onward, we assessed 1214 Chinese secondary school adolescents (60.7% were boys, aged 13-19 years) three times, 6 months apart. RESULTS: In the direct effects model, sleep problems were found to have a positive impact on adolescent suicidal behavior. In the indirect effects model, we observed that sleep problems were associated with an elevated risk of suicidal behavior through several pathways: one-mediator path of negative emotions, low self-control, and NSSI, respectively; two-mediator path of negative emotions via low self-control, negative emotions via NSSI, and low self-control via NSSI, and three-mediator path from negative emotions to NSSI via low self-control. CONCLUSIONS: This longitudinal study provides evidence that sleep problems in adolescents may increase suicidal behavior by exacerbating negative emotions, weakening self-control, and promoting NSSI. The findings suggest sleep problems should be addressed in suicide prevention and intervention efforts for adolescents.

Contribution of mono- and co-culture of Pseudomonas paralactis, Acinetobacter MN21 and Stenotrophomonas maltophilia to the spoilage of chill-stored lamb.

Exploring the contribution of common microorganisms to spoilage is of great significance in inhibiting spoilage in lamb. This work investigated the extent of protein degradation and profile changes of free amino acids (FAAs), free fatty acids (FFAs) and volatile organic compounds (VOCs) in lamb caused by single- and co-culture of the common aerobic spoilage bacteria, P. paralactis, Ac. MN21 and S. maltophilia. Meanwhile, some key VOCs produced by the three bacteria during lamb spoilage were also screened by orthogonal partial least square discriminant analysis and difference value in VOCs content between inoculated groups and sterile group. Lamb inoculated with P. paralactis had the higher total viable counts, pH, total volatile base nitrogen and TCA-soluble peptides than those with the other two bacteria. Some FAAs and FFAs could be uniquely degraded by P. paralactis but not Ac. MN21 and S. maltophilia, such as Arg, Glu, C15:0, C18:0 and C18:1n9t. Co-culture of the three bacteria significantly promoted the overall spoilage, including bacterial growth, proteolysis and lipolysis. Key VOCs produced by P. paralactis were 2, 3-octanedione, those by Ac. MN21 were 1-octanol, octanal, hexanoic acid, 1-pentanol and hexanoic acid methyl ester, and that by S. maltophilia were hexanoic acid. The production of extensive key-VOCs was significantly and negatively correlated with C20:0, C23:0 and C18:ln9t degradation. This study can provide a basis for inhibiting common spoilage bacteria and promoting high-quality processing of fresh lamb.

Effects of different cold chain logistics modes on the quality and bacterial community succession of fresh pork.

The connection and temperature control of cold chain links are key to ensuring meat quality. Considering the practical production of cold chain logistics in China, this study investigated the impact of various cold chain logistics modes (including warehousing, transportation, and sales conditions) at different temperature settings (7 °C, 4 °C, and - 1 °C), modeled in the laboratory, on the quality and bacterial community succession of pork. The pork quality was evaluated by pH, water holding capacity, total volatile basic nitrogen (TVB-N), total viable count (TVC) and myowater status. Among the different cold chain logistics modes, the LL1 (samples being warehoused and transported at 4 °C for 96 h and sold at -1 °C) and the SL1 (samples being warehoused and transported at 4 °C for 30 h and sold at -1 °C) modes were suitable for inter-provincial and intra-provincial transportation due to their long shelf life (> 14 days), respectively. The bacterial community succession of pork in different cold chain logistics modes was accessed by high-throughput sequencing. The results indicated that the cold chain logistics modes had affected the bacterial community, with Latilactobacillus being the dominant bacteria in the LL1 mode and SL1 mode during spoilage. The study revealed that the entire or partial process supercooling treatment (-1 °C) during the cold chain logistics process could effectively preserve the meat quality, supporting the high-quality development of the fresh meat cold chain logistics.

Zein and tannic acid hybrid particles improving physical stability, controlled release properties, and antimicrobial activity of cinnamon essential oil loaded Pickering emulsions.

Pickering emulsion loading essential oil has demonstrated a promising strategy as delivery system in food preservation, but localization in stability and antimicrobial activity limits application. In this study, Pickering emulsions co-loaded with tannic acid and cinnamon essential oil (ZTC) have been developed based on zein and tannic acid complexes (ZT) mediated interfacial engineering. Fourier transform infrared, fluorescence spectroscopy, and molecular docking results indicated tannic acid altered the structural of zein. Interfacial tension results indicated that tannic acid accelerated the adsorbed speed of zein particles by decreased interfacial tension (11.99-9.96 mN/m). ZT5 formed a viscoelastic and dense layer in oil-water interface than that for other ZTs, which improved stability and control release performance of ZTC. Furthermore, the ZTC showed an effective antimicrobial activity against spoilage organisms Pseudomonad paralactis MN10 and Lactobacillus sakei VMR17. These findings provide new insight for developing co-loaded multiple antimicrobial agents within Pickering emulsion as a delivery system.

Inflammation in the COVID-19 airway is due to inhibition of CFTR signaling by the SARS-CoV-2 spike protein.

SARS-CoV-2-contributes to sickness and death in COVID-19 patients partly by inducing a hyper-proinflammatory immune response in the host airway. This hyper-proinflammatory state involves activation of signaling by NFκB, and unexpectedly, ENaC, the epithelial sodium channel. Post-infection inflammation may also contribute to "Long COVID"/PASC. Enhanced signaling by NFκB and ENaC also marks the airway of patients suffering from cystic fibrosis, a life-limiting proinflammatory genetic disease due to inactivating mutations in the CFTR gene. We therefore hypothesized that inflammation in the COVID-19 airway might similarly be due to inhibition of CFTR signaling by SARS-CoV-2 spike protein, and therefore activation of both NFκB and ENaC signaling. We used western blot and electrophysiological techniques, and an organoid model of normal airway epithelia, differentiated on an air-liquid-interface (ALI). We found that CFTR protein expression and CFTR cAMP-activated chloride channel activity were lost when the model epithelium was exposed to SARS-CoV-2 spike proteins. As hypothesized, the absence of CFTR led to activation of both TNFα/NFκB signaling and α and γ ENaC. We had previously shown that the cardiac glycoside drugs digoxin, digitoxin and ouabain blocked interaction of spike protein and ACE2. Consistently, addition of 30 nM concentrations of the cardiac glycoside drugs, prevented loss of both CFTR protein and CFTR channel activity. ACE2 and CFTR were found to co-immunoprecipitate in both basal cells and differentiated epithelia. Thus spike-dependent CFTR loss might involve ACE2 as a bridge between Spike and CFTR. In addition, spike exposure to the epithelia resulted in failure of endosomal recycling to return CFTR to the plasma membrane. Thus, failure of CFTR recovery from endosomal recycling might be a mechanism for spike-dependent loss of CFTR. Finally, we found that authentic SARS-CoV-2 virus infection induced loss of CFTR protein, which was rescued by the cardiac glycoside drugs digitoxin and ouabain. Based on experiments with this organoid model of small airway epithelia, and comparisons with 16HBE14o- and other cell types expressing normal CFTR, we predict that inflammation in the COVID-19 airway may be mediated by inhibition of CFTR signaling by the SARS-CoV-2 spike protein, thus inducing a cystic fibrosis-like clinical phenotype. To our knowledge this is the first time COVID-19 airway inflammation has been experimentally traced in normal subjects to a contribution from SARS-CoV-2 spike-dependent inhibition of CFTR signaling.

Poly[[tetra-aquadi-µ4-fumarato-µ2-oxalato-dierbium(III)] tetra-hydrate].

The title compound, {[Er2(C4H2O4)2(C2O4)(H2O)4]·4H2O} n , was synthesized by the reaction of erbium nitrate hexa-hydrate with fumaric acid and oxalic acid under hydro-thermal conditions. The Er(3+) cation (site symmetry ..2) is eight-coordinated by six O atoms from four fumarate anions (site symmetry ..2) and one bidentate oxalate anion (site symmetry 222), and by two water mol-ecules. The complex exhibits a three-dimensional structure consisting of oxalate pillared Er-fumarate layers with channels occupied by coordinating and lattice water mol-ecules. The three-dimensional structure features by Owater-H⋯O hydrogen bonds involving both the coordinating and lattice water mol-ecules.

Harsh Childhood Discipline and Developmental Changes in Adolescent Aggressive Behavior: The Mediating Role of Self-Compassion.

Harsh discipline during childhood (psychological aggression and corporal punishment) has been found to be an early risk factor for adolescent aggressive behavior. However, previous studies have mainly examined the relationship between harsh discipline as a whole and the level of adolescent aggressive behavior. This study investigates the effects of childhood psychological aggression and corporal punishment on the initial levels and rate of change in adolescent aggressive behavior, as well as the mediating role of self-compassion in this relationship. Using cluster sampling, a three-wave follow-up assessment was conducted on 1214 high-school students (60.7% boys; mean age at Wave 1 = 15.46 ± 0.71). The results showed that childhood psychological aggression and corporal punishment had a positive predictive effect on the development level of adolescent aggressive behavior. However, only childhood psychological aggression significantly directly attenuated the decline rate of adolescent aggressive behavior. In addition, both childhood psychological aggression and corporal punishment indirectly affected the initial levels and growth rate of adolescent aggressive behavior through self-compassion. These findings could provide potential targets for prevention and intervention programs aimed at improving aggressive behavior in Chinese adolescents.