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Abstract Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRβ-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis.

Abstract Background Abnormal lipid metabolism has recently been reported as a crucial signature of idiopathic pulmonary fibrosis (IPF). However, the origin and biological function of the lipid and possible mechanisms of increased lipid content in the pathogenesis of IPF remains undetermined. Methods Oil-red staining and immunofluorescence analysis were used to detect lipid accumulation in mouse lung fibrosis frozen sections, Bleomycin-treated human type II alveolar epithelial cells (AECIIs) and lung fibroblast. Untargeted Lipid omics analysis was applied to investigate differential lipid species and identified LysoPC was utilized to treat human lung fibroblasts and mice. Microarray and single-cell RNA expression data sets identified lipid metabolism-related differentially expressed genes. Gain of function experiment was used to study the function of 3-hydroxy-3-methylglutaryl-Coa Synthase 2 (HMGCS2) in regulating AECIIs lipid metabolism. Mice with AECII-HMGCS2 high were established by intratracheally delivering HBAAV2/6-SFTPC- HMGCS2 adeno-associated virus. Western blot, Co-immunoprecipitation, immunofluorescence, site-directed mutation and flow cytometry were utilized to investigate the mechanisms of HMGCS2-mediated lipid metabolism in AECIIs. Results Injured AECIIs were the primary source of accumulated lipids in response to Bleomycin stimulation. LysoPCs released by injured AECIIs could activate lung fibroblasts, thus promoting the progression of pulmonary fibrosis. Mechanistically, HMGCS2 was decreased explicitly in AECIIs and ectopic expression of HMGCS2 in AECIIs using the AAV system significantly alleviated experimental mouse lung fibrosis progression via modulating lipid degradation in AECIIs through promoting CPT1A and CPT2 expression by interacting with PPARα. Conclusions These data unveiled a novel etiological mechanism of HMGCS2-mediated AECII lipid metabolism in the genesis and development of pulmonary fibrosis and provided a novel target for clinical intervention.

De novo nucleotide biosynthetic pathway is a highly conserved and essential biochemical pathway in almost all organisms. Both purine nucleotides and pyrimidine nucleotides are necessary for cell metabolism and proliferation. Thus, the dysregulation of the de novo nucleotide biosynthetic pathway contributes to the development of many human diseases, such as cancer. It has been shown that many enzymes in this pathway are overactivated in different cancers. In this review, we summarize and update the current knowledge on the de novo nucleotide biosynthetic pathway, regulatory mechanisms, its role in tumorigenesis, and potential targeting opportunities.

As high-speed big-data communications impose new requirements on storage latency, low-density parity-check (LDPC) codes have become a widely used technology in flash-memory channels. However, the iterative LDPC decoding algorithm faces a high decoding latency problem due to its mechanism based on iterative message transmission. Motivated by the unbalanced bit reliability of codeword, this paper proposes two technologies, i.e., serial entropy feature-based layered normalized min-sum (S-EFB-LNMS) decoding and parallel entropy feature-based layered normalized min-sum (P-EFB-LNMS) decoding. First, we construct an entropy feature vector that reflects the real-time bit reliability of the codeword. Then, the reliability of the output information of the layered processing unit (LPU) is evaluated by analyzing the similarity between the check matrix and the entropy feature vector. Based on this evaluation, we can dynamically allocate and schedule LPUs during the decoding iteration process, thereby optimizing the entire decoding process. Experimental results show that these techniques can significantly reduce decoding latency.

Abstract Background Intestinal health plays a pivotal role in broiler chicken growth. Oregano aqueous extract (OAE) effectively exerts anti-inflammatory and antibacterial effects. However, the protective effects of OAE on intestinal health in broilers and the underlying mechanism remain unclear. This study aimed to investigate the potential effects of OAE on growth performance, the gut microbiota and intestinal health. A total of 840 1-d-old male and female broilers (Arbor Acres) were randomly allocated into 6 groups as follows: basal diet (Con), Con + antibiotics (Anti, colistin sulfate 7 g/kg, roxarsone 35 g/kg), Con + 400, 500, 600 and 700 mg/kg OAE (OAE400, OAE500, OAE600 and OAE700). Subsequently, fermentation in vitro together with oral administration trials were carried out to further assess the function of OAE on intestinal health of broilers. Results Dietary 700 mg/kg OAE supplementation resulted in an increase (P

Abstract Severe sleep deprivation (SD) has been highly associated with systemic energy wasting, such as lipid loss and glycogen depletion. Despite immune dysregulation and neurotoxicity observed in SD animals, whether and how the gut-secreted hormones participate in SD-induced disruption of energy homeostasis remains largely unknown. Using Drosophila as a conserved model organism, we characterize that production of intestinal Allatostatin A (AstA), a major gut-peptide hormone, is robustly increased in adult flies bearing severe SD. Interestingly, the removal of AstA production in the gut using specific drivers significantly improves lipid loss and glycogen depletion in SD flies without affecting sleep homeostasis. We reveal the molecular mechanisms whereby gut AstA promotes the release of an adipokinetic hormone (Akh), an insulin counter-regulatory hormone functionally equivalent to mammalian glucagon, to mobilize systemic energy reserves by remotely targeting its receptor AstA-R2 in Akh-producing cells. Similar regulation of glucagon secretion and energy wasting by AstA/galanin is also observed in SD mice. Further, integrating single-cell RNA sequencing and genetic validation, we uncover that severe SD results in ROS accumulation in the gut to augment AstA production via TrpA1. Altogether, our results demonstrate the essential roles of the gut-peptide hormone AstA in mediating SD-associated energy wasting.

Intensive selective breeding for high growth rate and body weight cause excess abdominal fat in broilers. Gut microbiota and folic acid were reported to regulate lipid metabolism. A total of 210 one-day-old broilers were divided into the control (folic acid at 1.3 mg/kg) and folic acid groups (folic acid at 13 mg/kg) to illustrate the effects of folic acid on growth performance, abdominal fat deposition, and gut microbiota, and the experiment lasted 28 d. Results revealed that dietary folic acid addition decreased abdominal fat percentage (P

Miscible CO2 flooding has shown bright prospects for improving oil recovery from unconventional reservoirs as well as for storing greenhouse gas in underground formations. Although the favorable water presence effect has been reported in the near miscible CO2 flooding practices, there is still a lack of target research works on the impact of water on the miscibility characteristics of the oil/gas systems. Therefore in this paper, the effect of water presence on the Minimum Miscibility Pressure (MMP) of the CO2/n-Hexadecane (n-C16H34) system is experimentally investigated based on the Oil Droplet Volume Measurement (ODVM) method. By pre-saturating CO2 with water in the high-pressure high-temperature cell, the water component is introduced at the CO2/oil interface. Measurement results show the water presence could result in lower MMPs of the CO2/oil system. Under five temperature levels of 40 °C, 51 °C, 61 °C, 72 °C, and 82 °C, the water presence decreases the MMPs of the CO2/n-C16H34 system from 8.2 to 7.8 MPa, from 9.6 to 8.8 MPa, from 11.6 to 10.2 MPa, from 13.0 MPa to 12.2 MPa and from 14.6 MPa to 13.2 MPa respectively. Thermodynamic calculations provide consistent results as the experimental observations, indicating the main mechanism behind the lower MMPs of the water presence CO2/oil system could be the decreased CO2 molar fraction in the water presence system. This research is expected to provide an innovative viewpoint to understand the water presence effect in the CO2 flooding processes.

Abstract The endogenous cyclic tetradecapeptide SST14 was reported to stimulate all five somatostatin receptors (SSTR1–5) for hormone release, neurotransmission, cell growth arrest and cancer suppression. Two SST14-derived short cyclic SST analogues (lanreotide or octreotide) with improved stability and longer lifetime were developed as drugs to preferentially activate SSTR2 and treat acromegalia and neuroendocrine tumors. Here, cryo-EM structures of the human SSTR2–Gi complex bound with SST14, octreotide or lanreotide were determined at resolutions of 2.85 Å, 2.97 Å, and 2.87 Å, respectively. Structural and functional analysis revealed that interactions between β-turn residues in SST analogues and transmembrane SSTR2 residues in the ligand-binding pocket are crucial for receptor binding and functional stimulation of the two SST14-derived cyclic octapeptides. Additionally, Q1022.63, N2766.55, and F2947.35 could be responsible for the selectivity of lanreotide or octreotide for SSTR2 over SSTR1 or SSTR4. These results provide valuable insights into further rational development of SST analogue drugs targeting SSTR2.

BackgroundCancer-associated fibroblasts (CAFs) are the important component of the tumor microenvironment (TME). Previous studies have found that some pro-malignant CAFs participate in the resistance to radiotherapy as well as the initiation and progression of tumor recurrence. However, the exact mechanism of how radiation affects CAFs remains unclear. This study aimed to explore the effect and possible mechanism of radiation-activated CAFs, and its influence on lung cancer.MethodsCAFs were isolated from surgical specimens in situ and irradiated with 8Gy x-rays. The changes in cell morphology and subcellular structure were observed. CAFs marker proteins such as FAP and α-SMA were detected by Western Blotting. Cell counting kit-8 (CCK8) assay, flow cytometry, wound healing assay, and transwell chamber assay was used to detect the activation of cell viability and migration ability. A nude mouse xenograft model was established to observe the tumorigenicity of irradiated CAFs in vivo. The genomic changes of CAFs after radiation activation were analyzed by transcriptome sequencing technology, and the possible mechanisms were analyzed.ResultsThe CAFs showed a disorderly growth pattern after X-ray irradiation. Subcellular observations suggested that metabolism-related organelles exhibited more activity. The expression level of CAFs-related signature molecules was also increased. The CAFs irradiated by 8Gy had good proliferative activity. In the (indirect) co-culture system, CAFs showed radiation protection and migration induction to lung cancer cell lines, and this influence was more obvious in radiation-activated CAFs. The radiation protection was decreased after exosome inhibitors were applied. Vivo study also showed that radiation-activated CAFs have stronger tumorigenesis. Transcriptome analysis showed that genes were enriched in several pro-cancer signaling pathways in radiation-activated CAFs.ConclusionsOur study confirmed that CAFs could be activated by ionizing radiation. Irradiation-activated CAFs could promote cancer cell proliferation, migration, radiotherapy tolerance, and tumorigenesis. These results suggested that irradiation-activated CAFs might participate in the recurrence of lung cancer after radiotherapy, and the inhibition of CAFs activation may be an important way to improve clinical radiotherapy efficacy.

BackgroundAbout170 chemical modifications to RNAs have been identified, which significantly affect gene expression. Dysregulation of RNA modifications induced by abnormal expression or mutations in RNA modifiers might result in cancer. The most frequent RNA modifications are N6-methyladenosine (m6A), 5-methylcytosine (m5C), and N7-methylguanosine (m7G). Lung cancer is the leading cause of cancer-related deaths globally. The present study aimed to investigate whether the expression of the m7G-related genes is linked to lung cancer cases with lung adenocarcinoma (LUAD), which accounts for about 40% of lung cancer cases.MethodsA total of 12 m7G-related differentially expressed genes (DEGs) were identified in LUAD patients by The Cancer Genome Atlas (TCGA). The least absolute shrinkage and selection operator (LASSO) Cox regression method was used to build a four-gene risk model. Then, LUAD patients in the TCGA cohort were divided into low- and high-risk groups based on their risk scores for subsequent molecular and clinical research.ResultsCompared to the low-risk group, the high-risk group had a decreased overall survival (OS) (P=0.047). The risk score and stage were independent factors for predicting the OS of LUAD (P=0.0004 and P

In this paper, two sandstone cores with permeabilities of 1.7mD and 2.6mD were employed and the ScCO2 huff-n-puff processes were carried out to check the oil recovery efficiency as well as the oil mobilization laws under the conditions of 50 °C and 25 MPa. Both cores were cut half after the completion of the process and the residue oil distribution in the entire core as well as the front half and back half of the core were scrutinized with help of the Nuclear Magnetic Resonance (NMR) measurements. It is found longer soaking time of 5 days leads to higher oil recovery rate of 17.2% in comparison with 15.2% after 1 day’s operation time. NMR measurement results show that more oil in the large pore spaces of the core is produced, while the oil in the small pore spaces is rarely mobilized after the ScCO2 huff-n-puff process. NMR results further show that the oil saturation in the large pores of the front part is obviously lower than that of the back part of the core, which indicates that a round of huff and puff operation mainly produced the oil in the large pore spaces from the front part of the core, while leave a considerable part of the oil undeveloped in the rear part of the core.

Purpose: Radiation pneumonitis (RP) frequently occurs during a treatment course of chest radiotherapy, which significantly reduces the clinical outcome and efficacy of radiotherapy. The ability to easily predict RP before radiotherapy would allow this disease to be avoided.Methods and Materials: This study recruited 48 lung cancer patients requiring chest radiotherapy. For each participant, RNA sequencing (RNA-Seq) was performed on a peripheral blood sample before radiotherapy. The RNA-Seq data was then integrated into a genome-scale flux analysis to develop an RP scoring system for predicting the probability of occurrence of RP. Meanwhile, the clinical information and radiation dosimetric parameters of this cohort were collected for analysis of any statistical associations between these parameters and RP. A non-parametric rank sum test showed no significant difference between the predicted results from the RP score system and the clinically observed occurrence of RP in this cohort.Results: The results of the univariant analysis suggested that the tumor stage, exposure dose, and bilateral lung dose of V5 and V20 were significantly associated with the occurrence of RP. The results of the multivariant analysis suggested that the exposure doses of V5 and V20 were independent risk factors associated with RP and a level of RP ≥ 2, respectively. Thus, our results indicate that our RP scoring system could be applied to accurately predict the risk of RP before radiotherapy because the scores were highly consistent with the clinically observed occurrence of RP.Conclusion: Compared with the standard statistical methods, this genome-scale flux-based scoring system is more accurate, straightforward, and economical, and could therefore be of great significance when making clinical decisions for chest radiotherapy.

Radiation induced lung injury (RILI) is a serious complication in patients received thoracic radiotherapy. The main clinical symptom of RILI includes short of breath, low fever and cough, seriously affect the survival of patients. How to better prevent and treat RILI is an urgent problem. Target theory, cytokine theory, free radical theory, and vascular endothelial cell damage theory are the main mechanisms of RILI. Among them, reactive oxygen species (ROS) produced during radiotherapy can induce tissue damage throughout the course of RILI, and have a direct effect on both radiation pneumonitis and radiation-induced lung fibrosis. Anti-oxygen therapy including thiol compounds, antioxidant enzymes, and plant antioxidants have been applied in the prevention and treatment of RILI. This article reviews the research and application of antioxidant therapy in RILI.

Background The study was conducted to evaluate the feasibility of using malignant pleural effusion (MPE) as a substitute specimen for genetic testing and to determine the significance of genetic profiling of MPE tumor cells to monitor non‐small cell lung cancer (NSCLC) progression and therapeutic response. Methods We selected 168 NSCLC patients with MPE. We extracted MPE and enriched tumor cells using a custom‐designed device. EGFR mutations and ALK/ROS1 fusions were then detected by quantitative real‐time PCR, and the results were used to guide targeted therapy. We investigated drug responses through imaging. Results MPE tumor cells were detected in all patients. EGFR mutations and ALK/ROS1 rearrangements were detected in biopsy samples, treated MPE, and untreated MPE. We found that treated MPE had higher sensitivity and specificity than biopsy or untreated MPE. Among the 26 EGFR inhibitor patients, 13 showed a partial response, 7 had progressive disease, and 6 showed stable disease. Among the 16 patients that received ALK/ROS1 inhibitors, 8 had a partial response, 4 had progressive disease, and 4 showed stable disease. Conclusion Our study provides a new, less invasive, and highly repeatable method of analyzing MPE tumor cells in NSCLC that facilitates precision medicine and genetic testing.

Although CO2 huff-n-puff process has been widely employed as an efficient oil recovery and carbon storage technique in unconventional reservoirs, it suffers from the disadvantages of lack of availability near a large field and formation leakage due to the high CO2 mobility. Carbonated water injection (CWI) has been extensively studied as the alternative of CO2 injection process, but the laboratory studies concerning on CW huff-n-puff process is scarcely reported. In this paper, the oil recovery characteristics of CW huff-n-puff process has been scrutinized under reservoir conditions of 28 MPa and 65 °C together with NMR tests to reveal the oil mobilization rules in the tight cores. Comparative studies on CO2 huff-n-puff and water huff-n-puff process were also performed. It is found 4 rounds of CW huff-n-puff processes could recover considerable amount of 36.2% of the oil from the tight core. Although the recovery rate is lower than 55.4% for CO2 process but it is much higher than 14.4% of the water process. NMR T2 results reveal the oil in the large size pores of the tight cores are mobilized and recovered in early huff-n-puff cycles, whereas the oil from small size pores are collected in the later stage of the CW and CO2 huff-n-puff processes. The research results indicate the CW huff-n-puff process is promising for tight reservoir development.

Simulative experiments were carried out for CO2 foam flooding process in homogeneous porous media prepared with the sand packing method, and the CO2 foam seepage characteristics in porous media were studied with CT technology. CO2 foam flooding experiments were carried out under different packing sand sizes, different surfactant concentrations and different gas-liquid ratios. CT technology was employed to visualize the displacement process and to obtain the water saturation data along the sample, and the pressure distribution in the sample during the foam seepage process was measured at the same time. Experimental results show that, CO2 foam flooding has higher pressure drop and lower water saturation entrance effect in the porous media with lower average grain sizes; when surfactant concentrations are higher than CMC (Critical Micelle Concentration), the generated foam is stable, without showing obvious difference for the foam displacement efficiency in the sample, and water saturation entrance effect gradually decreases with increase of surfactant concentrations; improving gas-liquid ratio can lead to higher foam seepage pressure drop, but has little effect on residue water saturation after foam displacement. Key words: CO2 flooding, CO2 foam, flooding experiment, seepage characteristics, CT technology, EOR