DHX38 restricts chemoresistance by regulating the alternative pre-mRNA splicing of RELL2 in pancreatic ductal adenocarcinoma.

Intron retention plays an important role in cancer progression and chemotherapy resistance and seems to be essential for the maintenance of genome stability in cancer. Here, our goal was to analyze the role of receptor expressed in lymphoid tissue (Relt)-like 2 (RELL2) intron 4 retention in promoting pancreatic ductal adenocarcinoma (PDAC) progression. Our results showed that intron retention (IR) occurs at the fourth intron of RELL2 transcript in gemcitabine resistant PDAC cells, however, the regulatory mechanism and the clinical implications of IR of RELL2 are unclear. Firstly, we found that RELL2 plays an anti-oncogenic role in PDAC by performing in vitro functional assays including cell proliferation, GEM cytotoxicity assay and apoptosis. Subsequently, we identified the upstream gene of RELL2, DEAH-Box Helicase 38 (DHX38), and demonstrated the direct interaction between DHX38 and RELL2 by RIP-qPCR. We also found that altered expression of DHX38 resulted in corresponding changes in intron 4 retention of RELL2. Importantly, we unveiled that overexpression of DHX38 on the basis of knocking down of the fourth intron of RELL2 resulted in an impaired intron 4 intention. Overall, our study identified a new IR site in PDAC, which could be a possible target for PDAC therapy.

A combinatorial F box protein directed pathway controls TRAF adaptor stability to regulate inflammation.

Uncontrolled activation of tumor necrosis factor receptor-associated factor (TRAF) proteins may result in profound tissue injury by linking surface signals to cytokine release. Here we show that a ubiquitin E3 ligase component, Fbxo3, potently stimulates cytokine secretion from human inflammatory cells by destabilizing a sentinel TRAF inhibitor, Fbxl2. Fbxo3 and TRAF protein in circulation positively correlated with cytokine responses in subjects with sepsis, and we identified a polymorphism in human Fbxo3, with one variant being hypofunctional. A small-molecule inhibitor targeting Fbxo3 was sufficient to lessen severity of cytokine-driven inflammation in several mouse disease models. These studies identified a pathway of innate immunity that may be useful to detect subjects with altered immune responses during critical illness or provide a basis for therapeutic intervention targeting TRAF protein abundance.

Indole-3-Acetic Acid Protects Against Lipopolysaccharide-induced Endothelial Cell Dysfunction and Lung Injury through the Activation of USP40.

Lung microvascular endothelial cell (EC) dysfunction is the pathological hallmark of acute respiratory distress syndrome (ARDS). Heat shock protein 90 (HSP90) is a key regulator in control of endothelial barrier disruption and inflammation. Our recent study has demonstrated that ubiquitin-specific peptidase 40 (USP40) preserves endothelial integrity by targeting HSP90 for its deubiquitination and inactivation. Indole-3-acetic acid (IAA), a plant hormone of the auxin class, can also be catabolized from dietary tryptophan by the intestinal microbiota. Accumulating evidence suggests that IAA reduces oxidative stress and inflammation, and promotes intestinal barrier function. However, little is known about the role of IAA in endothelial cells and acute lung injury. In this study, we investigated the role of IAA in lung endothelial cell function in the context of acute lung injury. IAA exhibited EC barrier protection against LPS-induced reduction in transendothelial electrical resistance (TEER) and inflammatory responses. The underlying mechanism of IAA on EC protective effects were investigated by examining the influence of IAA on levels of HSP90 ubiquitination and USP40 activity. We identified that IAA, acting as a potential activator of USP40, reduces HSP90 ubiquitination, thereby protecting against LPS-induced inflammation in human lung microvascular endothelial cell (HLMVECs) as well as alleviating experimental lung injury. Furthermore, the EC protective effects of IAA against LPS-induced EC dysfunction and lung injury were abolished in USP40 deficient HLMVECs and lungs of USP40 EC specific knockout (USP40cdh5-ECKO) mice. Taken together, this study reveals that IAA protects against LPS-induced EC dysfunction and lung injury through the activation of USP40.

Integrative Multianalytical Model Based on Novel Plasma Protein Biomarkers for Distinguishing Lung Adenocarcinoma and Benign Pulmonary Nodules.

Given the pressing clinical problem of making a decision in diagnosis for subjects with pulmonary nodules, we aimed to discover novel plasma protein biomarkers for lung adenocarcinoma (LUAD) and benign pulmonary nodules (BPNs) and then develop an integrative multianalytical model to guide the clinical management of LUAD and BPN patients. Through label-free quantitative plasma proteomic analysis (data are available via ProteomeXchange with identifier PXD046731), 12 differentially expressed proteins (DEPs) in LUAD and BPN were screened. The diagnostic abilities of DEPs were validated in two independent validation cohorts. The results showed that the levels of three candidate proteins (PRDX2, PON1, and APOC3) were lower in the plasma of LUAD than in BPN. The three candidate proteins were combined with three promising computed tomography indicators (spiculation, vascular notch sign, and lobulation) and three traditional markers (CEA, CA125, and CYFRA21-1) to construct an integrative multianalytical model, which was effective in distinguishing LUAD from BPN, with an AUC of 0.904, a sensitivity of 81.44%, and a specificity of 90.14%. Moreover, the model possessed impressive diagnostic performance between early LUADs and BPNs, with the AUC, sensitivity, specificity, and accuracy of 0.868, 65.63%, 90.14%, and 82.52%, respectively. This model may be a useful auxiliary diagnostic tool for LUAD and BPN by achieving a better balance of sensitivity and specificity.

Performance of Nitrogen-Doped Carbon Nanoparticles Carrying FeNiCu as Bifunctional Electrocatalyst for Rechargeable Zinc-Air Battery.

Catalysts for zinc-air batteries (ZABs) must be stable over long-term charging-discharging cycles and exhibit bifunctional catalytic activity. In this study, by doping nitrogen-doped carbon (NC) materials with three metal atoms (Fe, Ni, and Cu), a single-atom-distributed FeNiCu-NC bifunctional catalyst is prepared. The catalyst includes Fe(Ni-doped)-N4 for the oxygen evolution reaction (OER), Fe(Cu-doped)-N4 for the oxygen reduction reaction (ORR), and the NiCu-NC catalytic structure for the oxygen reduction reaction (ORR) in the nitrogen-doped carbon nanoparticles. This single-atom distribution catalyst structure enhances the bifunctional catalytic activity. If a trimetallic single-atom catalyst is designed, it will surpass the typical bimetallic single-atom catcalyst. FeNiCu-NC exhibits outstanding performance as an electrocatalyst, with a half-wave potential (E1/2) of 0.876 V versus RHE, overpotential (Ej = 10) of 253 mV versus RHE at 10 mA cm-2, and a small potential gap (ΔE = 0.61 V). As the anode in a ZAB, FeNiCu-NC can undergo continuous charge-discharged cycles for 575 h without significant attenuation. This study presents a new method for achieving high-performance, low-cost ZABs via trimetallic single-atom doping.

F-box protein FBXL19-mediated ubiquitination and degradation of the receptor for IL-33 limits pulmonary inflammation.

The ST2L receptor for interleukin 33 (IL-33) mediates pulmonary inflammation and immune system-related disorders, such as asthma and rheumatoid arthritis. At present, very little is known about the molecular regulation of ST2L expression. Here we found that FBXL19, an 'orphan' member of the Skp1-Cullin-F-box family of E3 ubiquitin ligases, selectively bound to ST2L to mediate its polyubiquitination and elimination in the proteasome. Degradation of ST2L involved phosphorylation of ST2L at Ser442 catalyzed by the kinase GSK3ß. Overexpression of FBXL19 abrogated the proapoptotic and inflammatory effects of IL-33 and lessened the severity of lung injury in mouse models of pneumonia. Our results suggest that modulation of the IL-33-ST2L axis by ubiquitin ligases might serve as a unique strategy for lessening pulmonary inflammation.

The systematic role of pancreatic cancer exosomes: distant communication, liquid biopsy and future therapy.

Pancreatic cancer remains one of the most lethal diseases worldwide. Cancer-derived exosomes, benefiting from the protective role of the lipid membrane, exhibit remarkable stability in the circulatory system. These exosomes, released by tumor microenvironment, contain various biomolecules such as proteins, RNAs, and lipids that plays a pivotal role in mediating distant communication between the local pancreatic tumor and other organs or tissues. They facilitate the transfer of oncogenic factors to distant sites, contributing to the compromised body immune system, distant metastasis, diabetes, cachexia, and promoting a microenvironment conducive to tumor growth and metastasis in pancreatic cancer patients. Beyond their intrinsic roles, circulating exosomes in peripheral blood can be detected to facilitate accurate liquid biopsy. This approach offers a novel and promising method for the diagnosis and management of pancreatic cancer. Consequently, circulating exosomes are not only crucial mediators of systemic cell-cell communication during pancreatic cancer progression but also hold great potential as precise tools for pancreatic cancer management and treatment. Exosome-based liquid biopsy and therapy represent promising advancements in the diagnosis and treatment of pancreatic cancer. Exosomes can serve as drug delivery vehicles, enhancing the targeting and efficacy of anticancer treatments, modulating the immune system, and facilitating gene editing to suppress tumor growth. Ongoing research focuses on biomarker identification, drug delivery systems, and clinical trials to validate the safety and efficacy of exosome-based therapies, offering new possibilities for early diagnosis and precision treatment in pancreatic cancer. Leveraging the therapeutic potential of exosomes, including their ability to deliver targeted drugs and modulate immune responses, opens new avenues for innovative treatment strategies.

Noncanonical HIPPO/MST Signaling via BUB3 and FOXO Drives Pulmonary Vascular Cell Growth and Survival.

RATIONALE: The MSTs (mammalian Ste20-like kinases) 1/2 are members of the HIPPO pathway that act as growth suppressors in adult proliferative diseases. Pulmonary arterial hypertension (PAH) manifests by increased proliferation and survival of pulmonary vascular cells in small PAs, pulmonary vascular remodeling, and the rise of pulmonary arterial pressure. The role of MST1/2 in PAH is currently unknown. OBJECTIVE: To investigate the roles and mechanisms of the action of MST1 and MST2 in PAH. METHODS AND RESULTS: Using early-passage pulmonary vascular cells from PAH and nondiseased lungs and mice with smooth muscle-specific tamoxifen-inducible Mst1/2 knockdown, we found that, in contrast to canonical antiproliferative/proapoptotic roles, MST1/2 act as proproliferative/prosurvival molecules in human PAH pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts and support established pulmonary vascular remodeling and pulmonary hypertension in mice with SU5416/hypoxia-induced pulmonary hypertension. By using unbiased proteomic analysis, gain- and loss-of function approaches, and pharmacological inhibition of MST1/2 kinase activity by XMU-MP-1, we next evaluated mechanisms of regulation and function of MST1/2 in PAH pulmonary vascular cells. We found that, in PAH pulmonary arterial adventitial fibroblasts, the proproliferative function of MST1/2 is caused by IL-6-dependent MST1/2 overexpression, which induces PSMC6-dependent downregulation of forkhead homeobox type O 3 and hyperproliferation. In PAH pulmonary arterial vascular smooth muscle cells, MST1/2 acted via forming a disease-specific interaction with BUB3 and supported ECM (extracellular matrix)- and USP10-dependent BUB3 accumulation, upregulation of Akt-mTORC1, cell proliferation, and survival. Supporting our in vitro observations, smooth muscle-specific Mst1/2 knockdown halted upregulation of Akt-mTORC1 in small muscular PAs of mice with SU5416/hypoxia-induced pulmonary hypertension. CONCLUSIONS: Together, this study describes a novel proproliferative/prosurvival role of MST1/2 in PAH pulmonary vasculature, provides a novel mechanistic link from MST1/2 via BUB3 and forkhead homeobox type O to the abnormal proliferation and survival of pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts, remodeling and pulmonary hypertension, and suggests new target pathways for therapeutic intervention.

ISGylation of NF-κBp65 by SCFFBXL19 E3 Ligase Diminishes Endothelial Inflammation.

BACKGROUND: NF-κB (nuclear factor kappa B) plays a pivotal role in endothelial cell (EC) inflammation. Protein ISGylation is regulated by E3 ISG15 (interferon-stimulated gene 15) ligases; however, ISGylation of NF-κBp65 and its role in EC functions have not been investigated. Here, we investigate whether p65 is ISGylated and the role of its ISGylation in endothelial functions. METHODS: In vitro ISGylation assay and EC inflammation were performed. EC-specific transgenic mice were utilized in a murine model of acute lung injury. RESULTS: We find that NF-κBp65 is ISGylated in resting ECs and that the posttranslational modification is reversible. TNFα (tumor necrosis factor alpha) and endotoxin stimulation of EC reduce p65 ISGylation, promoting its serine phosphorylation through reducing its association with a phosphatase WIP1 (wild-type p53-induced phosphatase 1). Mechanistically, an SCF (Skp1-Cul1-F-box) protein E3 ligase SCFFBXL19 is identified as a new ISG15 E3 ligase that targets and catalyzes ISGylation of p65. Depletion of FBXL19 (F-box and leucine-rich repeat protein 19) increases p65 phosphorylation and EC inflammation, suggesting a negative correlation between p65 ISGylation and phosphorylation. Moreover, EC-specific FBXL19 overexpressing humanized transgenic mice exhibit reduced lung inflammation and severity of experimental acute lung injury. CONCLUSIONS: Together, our data reveal a new posttranslational modification of p65 catalyzed by a previously unrecognized role of SCFFBXL19 as an ISG15 E3 ligase that modulates EC inflammation.

CCDC12 gene methylation in peripheral blood as a potential biomarker for breast cancer detection.

BACKGROUND: Aberrant DNA methylation has been identified as biomarkers for breast cancer detection. Coiled-coil domain containing 12 gene (CCDC12) implicated in tumorigenesis. This study aims to investigate the potential of blood-based CCDC12 methylation for breast cancer detection. METHODS: DNA methylation level of CpG sites (Cytosine-phosphate Guanine dinucleotides) in CCDC12 gene was measured by mass spectrometry in 255 breast cancer patients, 155 patients with benign breast nodules and 302 healthy controls. The association between CCDC12 methylation and breast cancer risk was evaluated by logistic regression and receiver operating characteristic curve analysis. RESULTS: A total of eleven CpG sites were analyzed. The CCDC12 methylation levels were higher in breast cancer patients. Compared to the lowest tertile of methylation level in CpG_6,7, CpG_10 and CpG_11, the highest quartile was associated with 82, 91 and 95% increased breast cancer risk, respectively. The CCDC12 methylation levels were associated with estrogen receptor (ER) and human epidermal growth factor 2 (HER2) status. In ER-negative and HER2-positive (ER-/HER2+) breast cancer subtype, the combination of four sites CpG_2, CpG_5, CpG_6,7 and CpG_11 methylation levels could distinguish ER-/HER2+ breast cancer from the controls (AUC = 0.727). CONCLUSION: The hypermethylation levels of CCDC12 in peripheral blood could be used for breast cancer detection.

Breast cancer detection could be facilitated by novel blood-based DNA methylation biomarkers.The methylation levels of CpG sites in CCDC12 were higher in breast cancer than those in controls.The combination of four sites CpG_2, CpG_5, CpG_6,7 and CpG_11 methylation levels could distinguish ER-/HER2+ breast cancer subtype from the controls.

Maintaining moderate versus lower PEEP after cardiac surgery: a propensity-scored matched analysis.

BACKGROUND: Setting positive end-expiratory pressure (PEEP) at around 5 cm H2O in the early postoperative period seems a common practice for most patients. It remains unclear if the routine application of higher levels of PEEP confers any meaningful clinical benefit for cardiac surgical patients. The aim of this study was to compare moderate versus conventional lower PEEP on patient-centered outcomes in the intensive care unit (ICU). METHODS: This is a single-center retrospective study involving patients receiving cardiac surgery from June 2022 to May 2023. Propensity-score matching (PSM) was used to balance the baseline differences. Primary outcomes were the duration of mechanical ventilation and ICU length of stay. Secondary outcomes included PaO2/FiO2 ratio at 24 h and the need for prone positioning during ICU stay. RESULTS: A total of 334 patients were included in the study, 102 (31%) of them received moderate PEEP (≥ 7 cm H2O) for the major time in the early postoperative period (12 h). After PSM, 79 pairs of patients were matched with balanced baseline data. The results showed that there was marginal difference in the distribution of mechanical ventilation duration (p = 0.05) and the Moderate PEEP group had a higher extubation rate at the day of T-piece trial (65 [82.3%] vs 52 [65.8%], p = 0.029). Applying moderate PEEP was also associated with better oxygenation. No differences were found regarding ICU length of stay and patients requiring prone positioning between groups. CONCLUSION: In selective cardiac surgical patients, using moderate PEEP compared with conventional lower PEEP in the early postoperative period correlated to better oxygenation, which may have potential for earlier liberation of mechanical ventilation.

The association between high-oxygen saturation and prognosis for intracerebral hemorrhage.

BACKGROUND: Concerns about the adverse effects of excessive oxygen have grown over the years. This study investigated the relationship between high oxygen saturation and short-term prognosis of patients with spontaneous intracerebral hemorrhage (sICH) after liberal use of oxygen. METHODS: This retrospective cohort study collected data from the Medical Information Mart for Intensive Care III (MIMIC-III) database (ICU cohort) and a tertiary stroke center (general ward cohort). The data on pulse oximetry-derived oxygen saturation (SpO2) during the first 24 h in ICU and general wards were respectively extracted. RESULTS: Overall, 1117 and 372 patients were included in the ICU and general ward cohort, respectively. Among the patients from the ICU cohort, a spoon-shaped association was observed between minimum SpO2 and the risk of in-hospital mortality (non-linear P<0.0001). In comparison with minimum SpO2 of 93-97%, the minimum SpO2>97% was associated with a significantly higher risk of in-hospital mortality after adjustment for confounders. Sensitivity analysis conducted using propensity score matching did not change this significance. The same spoon-shaped association between minimum SpO2 and the risk of in-hospital mortality was also detected for the general ward cohort. In comparison with the group with 95-97% SpO2, the group with SpO2>97% showed a stronger association with, but non-significant risk for, in-hospital mortality after adjustment for confounders. The time-weighted average SpO2>97% was associated significantly with in-hospital mortality in both cohorts. CONCLUSION: Higher SpO2 (especially a minimum SpO2>97%) was unrewarding after liberal use of oxygen among patients with sICH and might even be potentially detrimental.

Venous resection increases risk of chyle leak after total pancreatectomy for pancreatic tumors.

BACKGROUND: Existing research on chyle leak (CL) after pancreatic surgery is mostly focused on pancreaticoduodenectomy and lacks investigation on total pancreatectomy (TP). This study aimed to explore potential risk factors of CL and develop a predictive model for patients with pancreatic tumor undergoing TP. METHODS: This retrospective study enrolled 90 consecutive patients undergoing TP from January 2015 to December 2023 at Peking Union Medical College Hospital. According to the inclusion criteria, 79 patients were finally included in the following analysis. The LASSO regression and multivariate logistic regression analysis were performed to identify risk factors associated with CL and construct a predictive nomogram. Then, the ROC analysis, calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were performed to assess its discrimination, accuracy, and efficacy. Due to the small sample size, we adopted the bootstrap resampling method with 500 repetitions for validation. Lastly, we plotted and analyzed the trend of postoperative drainage volume in CL patients. RESULTS: We revealed that venous resection (OR = 4.352, 95%CI 1.404-14.04, P = 0.011) was an independent risk factor for CL after TP. Prolonged operation time (OR = 1.473, 95%CI 1.015-2.237, P = 0.052) was also associated with an increased incidence of CL. We included these two factors in our prediction model. The area under the curve (AUC) was 0.752 (95%CI 0.622-0.874) after bootstrap. The calibration curve, DCA and CIC showed great accuracy and clinical benefit of our nomogram. In patients with CL, the mean drainage volume was significantly higher in venous resection group and grade B CL group. CONCLUSION: Venous resection was an independent risk factor for chyle leak after TP. Patients undergoing vascular resection during TP should be alert for the occurrence of CL after surgery. We then constructed a nomogram consisted of venous resection and operation time to predict the odds of CL in patients undergoing TP.

Oral administration of PEGylated TLR7 ligand ameliorates alcohol-associated liver disease via the induction of IL-22.

Effective therapies for alcohol-associated liver disease (ALD) are limited; therefore, the discovery of new therapeutic agents is greatly warranted. Toll-like receptor 7 (TLR7) is a pattern recognition receptor for single-stranded RNA, and its activation prevents liver fibrosis. We examined liver and intestinal damage in Tlr7-/- mice to determine the role of TLR7 in ALD pathogenesis. In an alcoholic hepatitis (AH) mouse model, hepatic steatosis, injury, and inflammation were induced by chronic binge ethanol feeding in mice, and Tlr7 deficiency exacerbated these effects. Because these results demonstrated that endogenous TLR7 signaling activation is protective in the AH mouse model, we hypothesized that TLR7 activation may be an effective therapeutic strategy for ALD. Therefore, we investigated the therapeutic effect of TLR7 agonistic agent, 1Z1, in the AH mouse model. Oral administration of 1Z1 was well tolerated and prevented intestinal barrier disruption and bacterial translocation, which thus suppressed ethanol-induced hepatic injury, steatosis, and inflammation. Furthermore, 1Z1 treatment up-regulated the expression of antimicrobial peptides, Reg3b and Reg3g, in the intestinal epithelium, which modulated the microbiome by decreasing and increasing the amount of Bacteroides and Lactobacillus, respectively. Additionally, 1Z1 up-regulated intestinal interleukin (IL)-22 expression. IL-22 deficiency abolished the protective effects of 1Z1 in ethanol-induced liver and intestinal damage, suggesting intestinal IL-22 as a crucial mediator for 1Z1-mediated protection in the AH mouse model. Collectively, our results indicate that TLR7 signaling exerts protective effects in the AH mouse model and that a TLR7 ligand, 1Z1, holds therapeutic potential for the treatment of AH.

Bridging the gap: Public engagement in blue-green space development for healthier urban futures.

BACKGROUND: With the rapid escalation of global urbanization, the role of blue-green spaces in urban ecology, public health, and planning has become increasingly prominent. Although their contributions to ecological preservation, public health, and urban design are widely acknowledged, research into public engagement and willingness to participate in the management and planning of these spaces is still in its early stages. OBJECTIVE: This study aims to identify key factors influencing public willingness to participate in blue-green space management, focusing specifically on people's perceptions of blue-green spaces (including perceived quality and accessibility), their usage behaviors (i.e., frequency of usage of blue-green spaces), and their self-assessed physical and mental health. METHODS: We interviewed local residents through random sampling to obtain sample data, and used a representative sample (n = 815, 510 women; 305 men, age 18-85 years, lived in Chengdu for an extensive time) of residents living in Chengdu City, China. Employing a quantitative approach, we examined the relationships between factors such as gender, regular occupation, income, behavior, and health status in relation to the willingness to participate. Additionally, we explored how perceptions and behaviors impacted health statuses and, consequently, inclinations to participate. RESULTS: The findings indicate that individuals with steady occupations and higher incomes are more inclined to engage in the management and planning of blue-green spaces. Notably, men exhibited a greater tendency to participate than women. Furthermore, access to blue-green spaces emerged as a crucial mechanism for addressing health disparities, offering significant implications for urban planning and public health. CONCLUSION: Successful blue-green space planning and understanding of willingness to participate necessitates the holistic consideration of people's perceptions of blue-green spaces, their usage behaviour and their self-rate health. For a tangible impact on health equity and global urban development, it's essential to prioritize blue-green spaces in planning, especially in lower-income regions. This not only promotes environmental perception but can also be a strategic approach to address health disparities. Our findings offer vital insights for tailoring international urban planning and management practices towards these goals.

Integrated transcriptome and proteome revealed that the declined expression of cell cycle-related genes associated with follicular atresia in geese.

BACKGROUND: Geese exhibit relatively low reproductive performance, and follicular atresia is an important factor that restricts the egg production of geese. Systematic analysis of the regulation of follicle atresia in geese through transcriptome and proteome levels could provide meaningful information on clarifying the mechanism of follicle atresia in poultry. RESULT: The granulosa cell layer was loose, disintegrated and showed apoptosis in atretic follicles and remained intact in normal follicles. The hormone levels of FSH and LH were significantly decreased in the atresia follicles compared to the normal follicles (P < 0.05). A total of 954 differentially expressed genes (DEGs, 315 increased and 639 decreased) and 161 differentially expressed proteins (DEPs, 61 increased and 100 decreased) were obtained in atresia follicles compared to normal follicles, of which, 15 genes were differentially expressed in both transcriptome and proteome. The DEGs were mainly enriched in sodium transmembrane transport, plasma membrane, and transmembrane transporter activity based on the GO enrichment analysis and in the cell cycle pathway based on the KEGG enrichment analysis. The DEPs were mainly enriched in localization, lysosome, and phospholipid-binding based on the GO enrichment analysis. Candidate genes Smad2/3, Smad4, Annexin A1 (ANXA1), Stromelysin-1 (MMP3), Serine/threonine-protein kinase (CHK1), DNA replication licensing factor (MCM3), Cyclin-A2 (CCNA2), mitotic spindle assembly checkpoint protein (MAD2), Cyclin-dependent kinase 1 (CDK1), fibroblast growth factor 12 (FGF12), and G1/S-specific cyclin-D1 (CCND1) were possibly responsible for the regulation of atresia. CONCLUSION: The cell cycle is an important pathway for the regulation of follicular atresia. Sodium outflow and high expression of MMP3 and MMP9 could be responsible for structural destruction and apoptosis of follicular cells.

EGR1 induces EMT in pancreatic cancer via a P300/SNAI2 pathway.

BACKGROUND: The prognosis of pancreatic cancer patients remains relatively poor. Although some patients would receive surgical resection, distant metastasis frequently occurs within one year. Epithelial-mesenchymal transition (EMT), as a pathological mechanism in cancer progression, contributed to the local and distant metastasis of pancreatic cancer. METHODS: Tissue microarray analysis and immunohistochemistry assays were used to compare the expression of EGR1 in pancreatic cancer and normal pancreatic tissues. Transwell chambers were used to evaluated the migration and invasion ability of cancer cells. Immunofluorescence was utilized to assess the expression of E-cadherin. ChIP-qPCR assay was applied to verify the combination of EGR1 and SNAI2 promoter sequences. Dual-luciferase reporter assay was used to detect the gene promoter activation. Co-IP assay was conducted to verify the interaction of EGR1 and p300/CBP. RESULTS: EGR1 was highly expressed in pancreatic cancer rather than normal pancreatic tissues and correlated with poor prognosis and cancer metastasis. EGR1 was proved to enhance the migration and invasion ability of pancreatic cells. Besides, EGR1 was positively correlated with EMT process in pancreatic cancer, via a SNAI2-dependent pathway. P300/CBP was found to play an auxiliary role in the transcriptional activation of the SNAI2 gene by EGR1. Finally, in vivo experiments also proved that EGR1 promoted liver metastasis of pancreatic cancer. CONCLUSION: Our findings implied the EMT-promoting effect of EGR1 in pancreatic cancer and revealed the intrinsic mechanism. Blocking the expression of EGR1 may be a new anticancer strategy for pancreatic cancer.

The Osaka prognostic score and Naples prognostic score: novel biomarkers for predicting short-term outcomes after spontaneous intracerebral hemorrhage.

OBJECTIVES: Poor immune-nutritional status has been associated with an unfavorable outcome in critical illness. The Osaka prognostic score (OPS) and the Naples prognostic score (NPS), based on inflammatory and nutritional status, has been shown to predict prognosis following cancer and other diseases. The aim of this study was to investigate the relationship between the OPS and NPS and the short-term outcomes of patients with intracerebral hemorrhage (ICH). METHODS: We retrospectively analyzed the clinical data of patients hospitalized with spontaneous ICH (n = 340) at The Second Affiliated Hospital of Chongqing Medical University between August 2016 and August 2021. Inclusion criteria included patients aged between 18 and 70, and if a blood sample was taken for laboratory testing within 24 h of admission (serum C-reactive protein, albumin, total cholesterol, and counts for neutrophils, lymphocytes, and monocytes were collected on admission). Exclusion criteria included a non-spontaneous cause of ICH and patient death during hospitalization. Patients were divided into four groups based on OPS or five groups according to NPS. Outcomes were evaluated by the modified Rankin Scale (mRS) at six months post-ICH hospitalization. An unfavorable outcome was defined as a mRS score ≥ 3. RESULTS: A total of 289 patients met our inclusion criteria. The unfavorable outcome group had older age, a lower Glasgow Coma Scale score, a higher rate of complications and cerebral herniation, a longer hospital stay, and higher OPS and NPS when compared with the favorable outcome group. Univariate analysis showed that both OPS and NPS were strongly correlated with mRS (r = 0.196,P < 0.001; r = 0.244, P = 0.001, respectively). Multivariate analysis further showed that OPS and NPS were both independent predictors of unfavorable outcomes for patients with ICH with adjusted odds ratios of 1.802 (95% confidence interval [CI]:1.140-2.847, P = 0.012) and 1.702 (95% CI: 1.225-2.635, P = 0.02), respectively. The area under the curve (AUC) of NPS for predicting a poor outcome was 0.732 (95% CI: 0.665-0.799), which was similar to the AUC of OPS 0.724 (95% CI: 0.657-0.792). CONCLUSIONS: In this cohort, a higher OPS and NPS on admission was associated with poor outcome at six months following ICH, supporting their potential role as markers for predicting the outcome of patients with ICH.

Secondary and Topological Structural Merge Prediction of Alpha-Helical Transmembrane Proteins Using a Hybrid Model Based on Hidden Markov and Long Short-Term Memory Neural Networks.

Alpha-helical transmembrane proteins (αTMPs) play essential roles in drug targeting and disease treatments. Due to the challenges of using experimental methods to determine their structure, αTMPs have far fewer known structures than soluble proteins. The topology of transmembrane proteins (TMPs) can determine the spatial conformation relative to the membrane, while the secondary structure helps to identify their functional domain. They are highly correlated on αTMPs sequences, and achieving a merge prediction is instructive for further understanding the structure and function of αTMPs. In this study, we implemented a hybrid model combining Deep Learning Neural Networks (DNNs) with a Class Hidden Markov Model (CHMM), namely HDNNtopss. DNNs extract rich contextual features through stacked attention-enhanced Bidirectional Long Short-Term Memory (BiLSTM) networks and Convolutional Neural Networks (CNNs), and CHMM captures state-associative temporal features. The hybrid model not only reasonably considers the probability of the state path but also has a fitting and feature-extraction capability for deep learning, which enables flexible prediction and makes the resulting sequence more biologically meaningful. It outperforms current advanced merge-prediction methods with a Q4 of 0.779 and an MCC of 0.673 on the independent test dataset, which have practical, solid significance. In comparison to advanced prediction methods for topological and secondary structures, it achieves the highest topology prediction with a Q2 of 0.884, which has a strong comprehensive performance. At the same time, we implemented a joint training method, Co-HDNNtopss, and achieved a good performance to provide an important reference for similar hybrid-model training.

High-value utilisation of PGM-containing residual oil: Recovery of inorganic acids, potassium, and PGMs using a zero-waste approach.

Residual oil containing platinum group metals (PGMs), which is under-researched, can easily pose resource waste and environmental risks. PGMs feature as scarce strategic metals, and inorganic acids and potassium salts are also considered valuable. An integrated process for the harmless treatment and recovery of useful resources from residual oil is proposed herein. This work developed a zero-waste process based on the study of the main components and characteristics of the PGM-containing residual oil. The process consists of three modules: pre-treatment for phase separation, liquid-phase resource utilisation, and solid-phase resource utilisation. Separating the residual oil into liquid and solid phases allows for the maximum recovery of valuable components. However, concerns about the accurate determination of valued components emerged. Findings revealed that Fe and Ni are highly susceptible to spectral interference in the PGMs test when using the inductively coupled plasma method. After studying 26 PGM emission lines, Ir 212.681 nm, Pd 342.124 nm, Pt 299.797 nm, and Rh 343.489 nm were reliably identified. Finally, formic acid (81.5 g/t), acetic acid (117.2 kg/t), propionic acid (291.9 kg/t), butyric acid (3.6 kg/t), potassium salt (553.3 kg/t), Ir (27.8 g/t), Pd (10960.0 g/t), Pt (193.1 g/t), and Rh (109.8 g/t) were successfully obtained from the PGM-containing residual oil. This study provides a helpful reference for the determination of PGM concentrations and high-value utilisation of PGM-containing residual oil.