Unraveling wheat's response to salt stress during early growth stages through transcriptomic analysis and co-expression network profiling.

BACKGROUND: Soil salinization is one of the vital factors threatening the world's food security. To reveal the biological mechanism of response to salt stress in wheat, this study was conducted to resolve the transcription level difference to salt stress between CM6005 (salt-tolerant) and KN9204 (salt-sensitive) at the germination and seedling stage. RESULTS: To investigate the molecular mechanism underlying salt tolerance in wheat, we conducted comprehensive transcriptome analyses at the seedling and germination stages. Two wheat cultivars, CM6005 (salt-tolerant) and KN9204 (salt-sensitive) were subjected to salt treatment, resulting in a total of 24 transcriptomes. Through expression-network analysis, we identified 17 modules, 16 and 13 of which highly correlate with salt tolerance-related phenotypes in the germination and seedling stages, respectively. Moreover, we identified candidate Hub genes associated with specific modules and explored their regulatory relationships using co-expression data. Enrichment analysis revealed specific enrichment of gibberellin-related terms and pathways in CM6005, highlighting the potential importance of gibberellin regulation in enhancing salt tolerance. In contrast, KN9204 exhibited specific enrichment in glutathione-related terms and activities, suggesting the involvement of glutathione-mediated antioxidant mechanisms in conferring resistance to salt stress. Additionally, glucose transport was found to be a fundamental mechanism for salt tolerance during wheat seedling and germination stages, indicating its potential universality in wheat. Wheat plants improve their resilience and productivity by utilizing adaptive mechanisms like adjusting osmotic balance, bolstering antioxidant defenses, accumulating compatible solutes, altering root morphology, and regulating hormones, enabling them to better withstand extended periods of salt stress. CONCLUSION: Through utilizing transcriptome-level analysis employing WGCNA, we have revealed a potential regulatory mechanism that governs the response to salt stress and recovery in wheat cultivars. Furthermore, we have identified key candidate central genes that play a crucial role in this mechanism. These central genes are likely to be vital components within the gene expression network associated with salt tolerance. The findings of this study strongly support the molecular breeding of salt-tolerant wheat, particularly by utilizing the genetic advancements based on CM6005 and KN9204.

Genome-scale CRISPR-Cas9 screen identifies PAICS as a therapeutic target for EGFR wild-type non-small cell lung cancer.

Epidermal growth factor receptor-targeted (EGFR-targeted) therapies show promise for non-small cell lung cancer (NSCLC), but they are ineffective in a third of patients who lack EGFR mutations. This underlines the need for personalized treatments for patients with EGFR wild-type NSCLC. A genome-wide CRISPR/Cas9 screen has identified the enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), which is vital in de novo purine biosynthesis and tumor development, as a potential drug target for EGFR wild-type NSCLC. We have further confirmed that PAICS expression is significantly increased in NSCLC tissues and correlates with poor patient prognosis. Knockdown of PAICS resulted in a marked reduction in both in vitro and in vivo proliferation of EGFR wild-type NSCLC cells. Additionally, PAICS silencing led to cell-cycle arrest in these cells, with genes involved in the cell cycle pathway being differentially expressed. Consistently, an increase in cell proliferation ability and colony number was observed in cells with upregulated PAICS in EGFR wild-type NSCLC. PAICS silencing also caused DNA damage and cell-cycle arrest by interacting with DNA repair genes. Moreover, decreased IMPDH2 activity and activated PI3K-AKT signaling were observed in NSCLC cells with EGFR mutations, which may compromise the effectiveness of PAICS knockdown. Therefore, PAICS plays an oncogenic role in EGFR wild-type NSCLC and represents a potential therapeutic target for this disease.

TNFRSF19 within the 13q12.12 Risk Locus Functions as a Lung Cancer Suppressor by Binding Wnt3a to Inhibit Wnt/ß-Catenin Signaling.

Cancer risk loci provide special clues for uncovering pathogenesis of cancers. The TNFRSF19 gene located within the 13q12.12 lung cancer risk locus encodes TNF receptor superfamily member 19 (TNFRSF19) protein and has been proved to be a key target gene of a lung tissue-specific tumor suppressive enhancer, but its functional role in lung cancer pathogenesis remains to be elucidated. Here we showed that the TNFRSF19 gene could protect human bronchial epithelial Beas-2B cells from pulmonary carcinogen nicotine-derived nitrosamine ketone (NNK)-induced malignant transformation. Knockout of the TNFRSF19 significantly increased NNK-induced colony formation rate on soft agar. Moreover, TNFRSF19 expression was significantly reduced in lung cancer tissues and cell lines. Restoration of TNFRSF19 expression in A549 lung cancer cell line dramatically suppressed the tumor formation in xenograft mouse model. Interestingly, the TNFRSF19 protein that is an orphan membrane receptor could compete with LRP6 to bind Wnt3a, thereby inhibiting the Wnt/ß-catenin signaling pathway that is required for NNK-induced malignant transformation as indicated by protein pulldown, site mutation, and fluorescence energy resonance transfer experiments. Knockout of the TNFRSF19 enhanced LRP6-Wnt3a interaction, promoting ß-catenin nucleus translocation and the downstream target gene expression, and thus sensitized the cells to NNK carcinogen. In conclusion, our study demonstrated that the TNFRSF19 inhibited lung cancer carcinogenesis by competing with LRP6 to combine with Wnt3a to inhibit the Wnt/ß-catenin signaling pathway. IMPLICATIONS: These findings revealed a novel anti-lung cancer mechanism, highlighting the special significance of TNFRSF19 gene within the 13q12.12 risk locus in lung cancer pathogenesis.

Prolonged exposure to environmental levels of microcystin-LR triggers ferroptosis in brain via the activation of Erk/MAPK signaling pathway.

While existing research has illuminated the environmental dangers and neurotoxic effects of MC-LR exposure, the molecular underpinnings of brain damage from environmentally-relevant MC-LR exposure remain elusive. Employing a comprehensive approach involving RNA sequencing, histopathological examination, and biochemical analyses, we discovered genes differentially expressed and enriched in the ferroptosis pathway. This finding was associated with mitochondrial structural impairment and downregulation of Gpx4 and Slc7a11 in mice brains subjected to low-dose MC-LR over 180 days. Mirroring these findings, we noted reduced cell viability and GSH/GSSH ratio, along with an increased ROS level, in HT-22, BV-2, and bEnd.3 cells following MC-LR exposure. Intriguingly, MC-LR also amplified phospho-Erk levels in both in vivo and in vitro settings, and the effects were mitigated by treatment with PD98059, an Erk inhibitor. Taken together, our findings implicate the activation of the Erk/MAPK signaling pathway in MC-LR-induced ferroptosis, shedding valuable light on the neurotoxic mechanisms of MC-LR. These insights could guide future strategies to prevent MC-induced neurodegenerative diseases.

Toward the next generation EGFR inhibitors: an overview of osimertinib resistance mediated by EGFR mutations in non-small cell lung cancer.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is currently the standard first-line therapy for EGFR-mutated advanced non-small cell lung cancer (NSCLC). The life quality and survival of this subgroup of patients were constantly improving owing to the continuous iteration and optimization of EGFR-TKI. Osimertinib, an oral, third-generation, irreversible EGFR-TKI, was initially approved for the treatment of NSCLC patients carrying EGFR T790M mutations, and has currently become the dominant first-line targeted therapy for most EGFR mutant lung cancer. Unfortunately, resistance to osimertinib inevitably develops during the treatment and therefore limits its long-term effectiveness. For both fundamental and clinical researchers, it stands for a major challenge to reveal the mechanism, and a dire need to develop novel therapeutics to overcome the resistance. In this article, we focus on the acquired resistance to osimertinib caused by EGFR mutations which account for approximately 1/3 of all reported resistance mechanisms. We also review the proposed therapeutic strategies for each type of mutation conferring resistance to osimertinib and give an outlook to the development of the next generation EGFR inhibitors. Video Abstract.

Evidence that oncostatin M synergizes with IL-4 signaling to induce TSLP expression in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Oncostatin M (OSM) may promote type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) by inducing thymic stromal lymphopoietin (TSLP). OBJECTIVE: We sought to study the impact of OSM on TSLP synthesis and release from nasal epithelial cells (NECs). METHODS: OSM receptors, IL-4 receptors (IL-4R), and TSLP were evaluated in mucosal tissue and primary NECs from patients with CRSwNP by quantitative PCR and immunofluorescence. Air-liquid interface-cultured NECs were stimulated with cytokines, including OSM, and quantitative PCR, ELISA, Western blot, and flow cytometry were used to assess the expression of OSM receptors, IL-4R, and TSLP. RESULTS: Increased levels of OSM receptor ß chain (OSMRß), IL-4Rα, and TSLP were observed in nasal polyp tissues and primary epithelial cells from nasal polyps of patients with CRSwNP compared with control tissues or cells from control subjects. The level of expression of OSMRß in tissue was correlated with levels of both IL-4Rα and TSLP. OSM stimulation of NECs increased the expression of OSMRß and IL-4Rα. Stimulation with IL-4 plus OSM augmented the production of TSLP; the response was suppressed by a signal transducer and activator of transcription 6 inhibitor. Stimulation of NECs with IL-4 plus OSM increased the expression of proprotein convertase subtilisin/kexin 3, an enzyme that truncates and activates TSLP. CONCLUSIONS: OSM increases the expression of IL-4Rα and synergizes with IL-4 to induce the synthesis and release of TSLP in NECs. Because the combination of IL-4 and OSM also augmented the expression of proprotein convertase subtilisin/kexin 3, these results suggest that OSM can induce both synthesis and posttranslational processing/activation of TSLP, promoting type 2 inflammation.

A Novel ATM Antisense Transcript ATM-AS Positively Regulates ATM Expression in Normal and Breast Cancer Cells.

OBJECTIVE: The ataxia telangiectasia mutated (ATM) gene is a master regulator in cellular DNA damage response. The dysregulation of ATM expression is frequent in breast cancer, and is known to be involved in the carcinogenesis and prognosis of cancer. However, the underlying mechanism remains unclear. The bioinformatic analysis predicted a potential antisense transcript ATM-antisense (AS) from the opposite strand of the ATM gene. The purpose of this study was to identify ATM-AS and investigate the possible effect of ATM-AS on the ATM gene regulation. METHODS: Single strand-specific RT-PCR was performed to verify the predicted antisense transcript ATM-AS within the ATM gene locus. qRT-PCR and Western blotting were used to detect the expression levels of ATM-AS and ATM in normal and breast cancer cell lines as well as in tissue samples. Luciferase reporter gene assays, biological mass spectrometry, ChIP-qPCR and RIP were used to explore the function of ATM-AS in regulating the ATM expression. Immunofluorescence and host-cell reactivation (HCR) assay were performed to evaluate the biological significance of ATM-AS in ATM-mediated DNA damage repair. Breast cancer tissue samples were used for evaluating the correlation of the ATM-AS level with the ATM expression as well as prognosis of the patients. RESULTS: The ATM-AS significantly upregulated the ATM gene activity by recruiting KAT5 histone acetyltransferase to the gene promoter. The reduced ATM-AS level led to the abnormal downregulation of ATM expression, and impaired the ATM-mediated DNA damage repair in normal breast cells in vitro. The ATM-AS level was positively correlated with the ATM expression in the examined breast cancer tissue samples, and the patient prognosis. CONCLUSION: The present study demonstrated that ATM-AS, an antisense transcript located within the ATM gene body, is an essential positive regulator of ATM expression, and functions by mediating the binding of KAT5 to the ATM promoter. These findings uncover the novel mechanism underlying the dysregulation of the ATM gene in breast cancer, and enrich our understanding of how an antisense transcript regulates its host gene.

Full-Length Transcriptome Analysis of the Halophyte Nitraria sibirica Pall.

BACKGROUND: Nitraria sibirica Pall. is one of the pioneer tree species in saline-alkali areas due to its extreme salt tolerance. However, the lack of information on its genome limits the further exploration of the molecular mechanisms in N. sibirica under salt stress. METHODS: In this study, we used single-molecule real-time (SMRT) technology based on the PacBio Iso-Seq platform to obtain transcriptome data from N. sibirica under salt treatment for the first time, which is helpful for our in-depth analysis of the salt tolerance and molecular characteristics of N. sibirica. RESULTS: Our results suggested that a total of 234,508 circular consensus sequences (CCSs) with a mean read length of 2121 bp were obtained from the 19.26 Gb raw data. Furthermore, based on transcript cluster analysis, 93,713 consensus isoforms were obtained, including 92,116 high-quality isoforms. After removing redundant sequences, 49,240 non-redundant transcripts were obtained from high-quality isoforms. A total of 37,261 SSRs, 1816 LncRNAs and 47,314 CDSs, of which 40,160 carried complete ORFs, were obtained. Based on our transcriptome data, we also analyzed the coding genes of H+-PPase, and the results of both bioinformatics and functional analyses indicated that the gene prediction via full-length transcripts obtained by SMRT technology is reliable and effective. In summary, our research data obtained by SMRT technology provides more reliable and accurate information for the further analysis of the regulatory network and molecular mechanism of N. sibirica under salt stress.

Maraviroc, an inhibitor of chemokine receptor type 5, alleviates neuroinflammatory response after cerebral Ischemia/reperfusion injury via regulating MAPK/NF-κB signaling.

Neuroinflammation is a key factor that contributes to the secondary damage after cerebral ischemia/reperfusion (CI/R) injury. Chemokine receptor type 5 (CCR5) has shown its pro-inflammatory effects during central nervous system (CNS) diseases. However, the role of CCR5 in CI/R injury is still unclear. In this study, we administered maraviroc (MVC, APEXBIO, UK-427857), a CCR5 antagonist, to the middle cerebral artery occlusion (MCAO) mice. In vivo studies showed that MVC was successively intraperitoneally (i.p.) injected with doses (20 mg/kg body weight) for 3 days after mice MCAO. MVC showed its neuroprotective effects in alleviating neurological deficits and infarct volumes after MCAO. The level of apoptosis and inflammation were remarkably decreased by MVC treatment after CI/R injury. Subsequently, primary microglia cells were stimulated with doses of MVC (20 nM) for 12 h after oxygen-glucose deprivation/reoxygenation model (OGD/R) in vitro. MVC significantly increased the viability of primary microglia after OGD/R. The expression of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) in microglia was down-regulated by MVC treatment. Mechanistically, MVC also inhibited the secretion of these cytokines by microglia after OGD stimulation. Furthermore, the key components of NF-κB pathway were measured in vivo and in vitro after MCAO and OGD. MVC significantly inhibited the activity of NF-κB pathway in the above pathological environments. Finally, our data indicated that MVC treatment decreased the activation of JNK signaling pathway after CI/R injury in vivo and in vitro. The JNK activator anisomycin (AN, Beyotime, SC0132) reversed the neuroprotective effects of MVC, indicating that the JNK pathway is involved in the anti-inflammatory and anti-apoptotic mechanisms of MVC in CI/R injury. Our data demonstrated that CCR5 inhibition exhibits neuroprotective effects after CI/R injury. MVC, which is widely used for HIV treatment by its anti-virus effect, is a potential drug for the treatment of ischemic stroke in the future clinical trials. MVC has been widely used in HIV treatment which showed its safety. Based on its anti-inflammatory and anti-apoptotic mechanisms, we speculate that MVC may be a potential drug for treating ischemic stroke in future clinical trials.

Studies on activation and regulation of the coagulation cascade in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Increased activation of the coagulation cascade and diminished fibrinolysis combine to promote fibrin deposition and polyp formation in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP). More information is needed concerning mechanisms of coagulation in CRSwNP. OBJECTIVE: We investigated the mechanisms as well as the initiation and regulation of coagulation cascade activation in CRS. METHODS: Samples were collected from 135 subjects with CRSwNP, 80 subjects with chronic CRS without nasal polyps (NP), and 65 control subjects. The levels of activated factor X (FXa), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex, tissue factor (TF), and TF pathway inhibitor (TFPI) were monitored in CRS by real-time PCR, ELISA, immunohistochemistry, or immunofluorescence. Heteromeric complexes of TF with activated factor VII (FVII) and TF with activated FVII and FXa were assessed by coimmunoprecipitation and Western blotting. RESULTS: Increased levels of FXa, F1+2, and thrombin-antithrombin complex were detected in NP tissue compared to uncinate tissue from CRS and control subjects. Although free TF protein levels were not increased in NP, immunoprecipitation of TF in NP tissue revealed increased complexes of TF with FVII. Local expression of FVII was detected in sinonasal mucosa, and the ratio of TFPI to FXa was lower in NP tissue. CONCLUSION: The coagulation cascade is associated with NP compared to control and uncinate tissue from CRS patients, and TF and FVII are produced locally in sinonasal mucosa in patients. TF and FVII can activate the extrinsic coagulation pathway, suggesting that this pathway may activate fibrin deposition in CRSwNP. Reduced formation of the complex of FXa and TFPI in NP may reduce natural suppression of the extrinsic coagulation pathway in CRSwNP.

Structural advances in sterol-sensing domain-containing proteins.

The sterol-sensing domain (SSD) is present in several membrane proteins that function in cholesterol metabolism, transport, and signaling. Recent progress in structural studies of SSD-containing proteins, such as sterol regulatory element-binding protein (SREBP)-cleavage activating protein (Scap), Patched, Niemann-Pick disease type C1 (NPC1), and related proteins, reveals a conserved core that is essential for their sterol-dependent functions. This domain, by its name, 'senses' the presence of sterol substrates through interactions and may modulate protein behaviors with changing sterol levels. We summarize recent advances in structural and mechanistic investigations of these proteins and propose to divide them to two classes: M for 'moderator' proteins that regulate sterol metabolism in response to membrane sterol levels, and T for 'transporter' proteins that harbor inner tunnels for cargo trafficking across cellular membranes.

The enhancer rare germline variation rs548071605 contributes to lung cancer development.

Rare germline variations contribute to the missing heritability of human complex diseases including cancers. Given their very low frequency, discovering and testing disease-causing rare germline variations remains challenging. The tag-single nucleotide polymorphism rs17728461 in 22q12.2 is highly associated with lung cancer risk. Here, we identified a functional rare germline variation rs548071605 (A>G) in a p65-responsive enhancer located within 22q12.2. The enhancer significantly promoted lung cancer cell proliferation in vitro and in a xenograft mouse model by upregulating the leukemia inhibitory factor (LIF) gene via the formation of a chromatin loop. Differential expression of LIF and its significant correlation with first progression survival time of patients further supported the lung cancer-driving effects of the 22q-Enh enhancer. Importantly, the rare variation was harbored in the p65 binding sequence and dramatically increased the enhancer activity by increasing responsiveness of the enhancer to p65 and B-cell lymphoma 3 protein, an oncoprotein that assisted the p65 binding. Our study revealed a regulatory rare germline variation with a potential lung cancer-driving role in the 22q12.2 risk region, providing intriguing clues for investigating the "missing heritability" of cancers, and also offered a useful experimental model for identifying causal rare variations.

Heritable Variants in the Chromosome 1q22 Locus Increase Gastric Cancer Risk via Altered Chromatin Looping and Increased UBAP2L Expression.

Genome-wide association studies (GWAS) have implicated the 1q22 gastric cancer risk locus in disease, but little is known about its underlying oncogenic functions. This study represents a systematic investigation of the biological significance and potential mechanism associated with the gastric cancer risk of SNP rs2075570(C>T) in 1q22. We identified two functional germline variations (rs2049805-C and rs2974931-G) in an active enhancer in a 64.8 kb high-linkage disequilibrium block of rs2075570. The enhancer upregulated ubiquitin associated protein 2 like (UBAP2L) gene expression over a 960 kb distance by chromatin looping. Gastric cancer tissues expressed significantly higher levels of UBAP2L than was observed in the matched noncancerous tissues, and the UBAP2L expression was negatively correlated with patient survival. Downregulation of UBAP2L inhibited the proliferation and invasion of human gastric cancer cells in vitro and in a xenograft mouse model. Notably, the two mutant variations significantly enforced the enhancer activity and UBAP2L expression. In conclusion, this study revealed two causal variations in the 1q22 region using tag-SNP rs2075570 as a genetic marker. These variations may affect the occurrence and progression of gastric cancer by reinforcing the expression of the 1q22-Enh enhancer-regulated UBAP2L target gene. IMPLICATIONS: Our study provides an important clue of how noncoding germline variations contribute to gastric cancer, which gives a novel insight into understanding the genetic mechanism of gastric cancer.

The neuroprotective effect of phillyrin in intracerebral hemorrhagic mice is produced by activation of the Nrf2 signaling pathway.

Phillyrin, a natural plant extract, has significant antioxidant and anti-apoptotic effects. However, its effect on intracerebral hemorrhage (ICH) remains unclear. In this study, we investigated a potential role for phillyrin in the regulation of the oxidative stress and apoptosis induced by ICH. A model of ICH was induced by collagenase IV (0.2 U in 1 µl sterile normal saline) in male C57BL/6J (B6) mice and different doses of phillyrin (5, 15, or 30 mg/kg) were intraperitoneally (i.p.) injected at 30 min, 6 h, and 22 h after modeling. We found that phillyrin significantly reduced neural function and lesion volume, improved injury of white and grey matter around the lesion, decreased apoptosis and oxidative stress, increased the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase 1(HO-1), NADPH quinone oxidoreductase 1 (NQO1) and Superoxide Dismutase-1(SOD-1) in vitro and in vivo, and protected neurons from the stimulation of hemin by promoting Nrf2 nuclear translocation. Treatment with ML385 (Nrf2 inhibitor) completely reversed the protective effects of phillyrin in vivo after ICH injury. Based on our findings, we conclude that phillyrin treatment alleviates ICH injury-induced apoptosis and oxidative stress via activation of the Nrf2 signaling pathway, highlighting a potential role for phillyrin as an ICH therapeutic.

Effect of pemetrexed on the efficacy, toxic reaction, and survival rate of patients with EGFR-TKI resistant moderate and advanced lung cancer.

OBJECTIVE: To explore the effect of pemetrexed on the efficacy, toxic reaction, and survival rate of patients with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistant moderate to advanced lung cancer. METHODS: A total of 86 patients with EGFR-TKI resistant moderate and advanced lung cancer in our hospital were divided by therapeutic drugs into a control group (39 patients) and pemetrexed group (47 patients). Differences in general data, clinical efficacy, immunoglobulin expression, tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) levels, tumor markers, toxic reaction, and survival rate between the two groups were analyzed. RESULTS: Similar expression levels of carcinoembryonic antigen, IL-6, carbohydrate antigen 125, TNF-α, carbohydrate antigen 153 and immunoglobulin were found in the control group and pemetrexed group before treatment (all P>0.05). Expression levels of the above indicators in all patients decreased one month after the end of treatment, and levels of immunoglobulin, inflammatory factors, and tumor markers in the control group were higher than those in the pemetrexed group (all P<0.05). Similar incidence rates of toxic reactions were shown in the two groups (P>0.05). Twelve months after the end of treatment, one-year survival rate was significantly higher in the pemetrexed group than in the control group (χ2=3.332, P=0.042). CONCLUSION: Pemetrexed can significantly improve the clinical efficacy in patients with EGFR-TKI resistant lung cancer, decrease the expression of inflammatory factors, tumor markers, and immunoglobulin in serum, has few side effects on the body, and prolongs the long-term survival rate.

Extracorporeal membrane oxygenation (ECMO) for acute exacerbations of chronic obstructive pulmonary disease: care modalities, experience, and precautions.

PURPOSE: The aim of this study was to summarize the care modalities, experiences, and corresponding precautions of ECMO for acute exacerbations of chronic obstructive pulmonary disease (COPD). METHODS: Seventy-three patients with acute exacerbations of COPD were enrolled, of whom 38 were treated with ECMO (experimental group) and 35 received conventional low-flow oxygen therapy, management of metabolic acidosis, infection control, bronchodilators for quick relief from severe spasms, and glucocorticoid-mediated suppression of inflammation (control group). The improvement in the patient's pulmonary ventilation and the incidence of complications were recorded. RESULTS: PaCO2 is lower in patients using ECMO, FEV1, FEV1/FVC, and FEV1% are significantly higher in the experimental group than in the control group, and the respiratory rate, heart rate, and CO2 saturation are significantly lower in patients in the experimental group (i.e., the experimental group) after oxygenation than in the control group, pH and O2 saturation are significantly higher in experimental group than in the control group, and the incidence of complications in experimental group is significantly higher than in the control group. CONCLUSION: ECMO significantly improves gas exchange in patients, but also increases the incidence of complications with the extension of usage, so the duration of ECMO support should be monitored and the complications should be prevented.

Structural basis for sterol sensing by Scap and Insig.

The sterol regulatory element-binding protein (SREBP) pathway monitors the cellular cholesterol level through sterol-regulated association between the SREBP cleavage-activating protein (Scap) and the insulin-induced gene (Insig). Despite structural determination of the Scap and Insig-2 complex bound to 25-hydroxycholesterol, the luminal domains of Scap remain unresolved. In this study, combining cryogenic electron microscopy (cryo-EM) analysis and artificial intelligence-facilitated structural prediction, we report the structure of the human Scap/Insig-2 complex purified in digitonin. The luminal domain loop 1 and a co-folded segment in loop 7 of Scap resemble those of the luminal/extracellular domain in NPC1 and related proteins, providing clues to the cholesterol-regulated interaction of loop 1 and loop 7. An additional luminal interface is observed between Scap and Insig. We also show that Scap(D428A), which inhibits SREBP activation even under sterol depletion, exhibits an identical conformation with the wild-type protein when complexed with Insig-2, and its constitutive suppression of the SREBP pathway may also involve a later step in protein trafficking.

A structure of human Scap bound to Insig-2 suggests how their interaction is regulated by sterols.

The sterol regulatory element-binding protein (SREBP) pathway controls cellular homeostasis of sterols. The key players in this pathway, Scap and Insig-1 and -2, are membrane-embedded sterol sensors. The 25-hydroxycholesterol (25HC)-dependent association of Scap and Insig acts as the master switch for the SREBP pathway. Here, we present cryo-electron microscopy analysis of the human Scap and Insig-2 complex in the presence of 25HC, with the transmembrane (TM) domains determined at an average resolution of 3.7 angstrom. The sterol-sensing domain in Scap and all six TMs in Insig-2 were resolved. A 25HC molecule is sandwiched between the S4 to S6 segments in Scap and TMs 3 and 4 in Insig-2 in the luminal leaflet of the membrane. Unwinding of the middle of the Scap-S4 segment is crucial for 25HC binding and Insig association.

Cold-inducible RNA-binding protein contributes to tissue remodeling in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Cold-inducible RNA-binding protein (CIRP) is a newly identified damage-associated molecular pattern molecule. Its roles beyond promoting inflammation and in human diseases are poorly understood. This study aimed to investigate the involvement of CIRP in chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: Immunohistochemistry, quantitative RT-PCR, and ELISA were used to detect the expression of CIRP and matrix metalloproteinases (MMPs) in sinonasal mucosal samples and nasal secretions. Human nasal epithelial cells (HNECs) and THP-1 cells, a human monocytic/macrophage cell line, were cultured to explore the regulation of CIRP expression and MMP expression. RESULTS: Cytoplasmic CIRP expression in nasal epithelial cells and CD68+ macrophages in sinonasal tissues, and CIRP levels in nasal secretions were significantly increased in both patients with eosinophilic and noneosinophilic CRSwNP as compared to those in control subjects. IL-4, IL-13, IL-10, IL-17A, TNF-α, Dermatophagoides pteronyssinus group 1, and lipopolysaccharide induced the production and secretion of CIRP from HNECs and macrophages differentiated from THP-1 cells. CIRP promoted MMP2, MMP7, MMP9, MMP12, and vascular endothelial growth factor A (VEGF-A) production from HNECs, macrophages differentiated from THP-1 cells, and polyp tissues, which was inhibited by the blocking antibody for Toll-like receptor 4, but not advanced glycation end products. The expression of MMPs and VEGF-A in tissues correlated with CIRP levels in nasal secretions in patients with CRSwNP. CONCLUSIONS: The upregulated production and release of CIRP from nasal epithelial cells and macrophages may contribute to the edema formation in both eosinophilic and noneosinophilic CRSwNP by inducing MMP and VEGF-A production from epithelial cells and macrophages.

Development of a New Method for Turbidity Measurement Using Two NIR Digital Cameras.

This paper proposes a new method of using two NIR digital cameras to measure water turbidity accurately and quickly. A measuring device based on an NIR camera and image processing software is designed. Two NIR cameras collect scattered and transmitted images when the NIR light is passing through the turbid solution. The average RGB values of 400 pixels in the central region of the image are obtained and converted into CIE Lab color space values. The water turbidity was measured by the functional relationship between turbidity and the corresponding color components (R, G, B, L, a, b, and grayscale). The results of comparison with a commercial turbidimeter show that this method has a high accuracy for the determination of standard solution with wider linear range and is consistent with the turbidimeter results for the measurement of real samples, which verifies the feasibility of this method.