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Abstract Background The Bucephalidae is a large family of digenean trematodes but most previous analyses of its phylogenetic position have relied on a single mitochondrial gene or morphological features. Mitochondrial genomes (mitogenomes) remain unavailable for the entire family. To address this, we sequenced the complete mitogenome of Dollfustrema vaneyi and analyzed the phylogenetic relationships with other trematodes. Results The circular genome of Dollfustrema vaneyi spanned 14,959 bp and contained 12 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and a major non-coding region. We used concatenated amino acid and nucleotide sequences of all 36 genes for phylogenetic analyses, conducted using MrBayes, IQ-TREE and PhyloBayes. We identified pronounced topological instability across different analyses. The addition of recently sequenced two mitogenomes for the Aspidogastrea subclass along with the use of a site-heterogeneous model stabilized the topology, particularly the positions of Azygiidae and Bucephalidae. The stabilized results indicated that Azygiidae was the closest lineage to Bucephalidae in the available dataset, and together, they clustered at the base of the Plagiorchiida. Conclusions Our study provides the first comprehensive description and annotation of the mitochondrial genome for the Bucephalidae family. The results indicate a close phylogenetic relationship between Azygiidae and Bucephalidae, and reveal their basal placement within the order Plagiorchiida. Furthermore, the inclusion of Aspidogastrea mitogenomes and the site-heterogeneous model significantly improved the topological stability. These data will provide key molecular resources for future taxonomic and phylogenetic studies of the family Bucephalidae.

ABSTRACTThe antipsychotic drug pimozide has been demonstrated to inhibit cancer. However, the precise anti-cancer mechanism of pimozide remains unclear. The purpose of this study was to investigate the effects of pimozide on human MCF-7 and MDA-MB-231 breast cancer cell lines, and the potential involvement in the RAF/ERK signaling. The effects of pimozide on cells were examined by 4,5-dimethylthiazol-2-yl-3,5-diphenylformazan, wound healing, colony formation, transwell assays, and caspase activity assay. Flow cytometry and acridine orange and ethidium bromide staining were performed to assess changes in cells. Transmission electron microscopy and monodansylcadaverine staining were used to observe autophagosomes. The cyclic adenosine monophosphate was evaluated using the FRET system. Immunohistochemistry, immunofluorescence, RNA interference, and western blot investigated the expression of proteins. Mechanistically, we focus on the RAF1/ERK signaling. We detected pimozide was docked to RAF1 by Schrodinger software. Pimozide down-regulated the phosphorylation of RAF1, ERK 1/2, Bcl-2, and Bcl-xl, up-regulated Bax, and cleaved caspase-9 to induce apoptosis. Pimozide might promote autophagy by up-regulating cAMP. The enhancement of autophagy increased the conversion of LC3-I to LC3-II and down-regulated p62 expression. But mTOR signaling was not involved in promoting autophagy. The knockdown of RAF1 expression induced autophagy and apoptosis in breast cancer cells, consistent with the results of pimozide or sorafenib alone. Blocked autophagy by chloroquine resulted in the impairment of pimozide-induced apoptosis. These data showed that pimozide inhibits breast cancer by regulating the RAF/ERK signaling pathway and might activate cAMP-induced autophagy to promote apoptosis and it may be a potential drug for breast cancer treatment.

IntroductionScorias spongiosa is an edible fungus.MethodsIn this study, a nontargeted metabonomic analysis was conducted on the fruiting bodies of this fungus at five growth stages, and the differences in metabolites and the related metabolic pathways during growth and development were analysed.ResultsThis study revealed that the five growth stages of S. spongiosa fruiting bodies were associated with 15 pathways. These 15 metabolic pathways are speculated to play important roles in the growth of S. spongiosa fruiting bodies. Eleven bioactive substances were identified among the differentially expressed compounds. The content of six bioactive substances was highest at the S1 growth stage among all the growth stages. The metabolites related to sugar metabolism were enriched in three main pathways: pentose and gluconate interconversions, the pentose phosphate pathway, and the citrate cycle (TCA cycle).DiscussionThese results suggested that the S1 growth stage can be selected as the harvest period of S. spongiosa in fruiting bodies to retain most of the bioactive substances. Pentose and gluconate interconversions, the pentose phosphate pathway, and the TCA cycle are related to changes in polysaccharide content during the growth of S. spongiosa fruiting bodies.

Abstract Microbiological Rapid On-Site Evaluation (M-ROSE) is based on smear staining and microscopic observation, providing critical references for the diagnosis and treatment of pulmonary infectious disease. Automatic identification of pathogens is the key to improving the quality and speed of M-ROSE. Recent advancements in deep learning have yielded numerous identification algorithms and datasets. However, most studies focus on artificially cultured bacteria and lack clinical data and algorithms. Therefore, we collected Gram-stained bacteria images from lower respiratory tract specimens of patients with lung infections in Chinese PLA General Hospital obtained by M-ROSE from 2018 to 2022 and desensitized images to produce 1705 images (4,912 × 3,684 pixels). A total of 4,833 cocci and 6,991 bacilli were manually labelled and differentiated into negative and positive. In addition, we applied the detection and segmentation networks for benchmark testing. Data and benchmark algorithms we provided that may benefit the study of automated bacterial identification in clinical specimens.

Background: STIL is an important cell cycle-regulating protein specifically recruited to the mitotic centrosome to promote the replication of centrioles in dividing cells. However, the potential role of STIL in the regulation of the biological functions of triple-negative breast cancer remains still unclear. Methods: We screened for differentially expressed STIL in the Cancer Genome Atlas database. The expression of STIL protein in 10 pairs of breast cancer tissues and adjacent normal tissues was further assessed by western blotting. Functionally, the knockdown and overexpression of STIL have been used to explore the effects of STIL on breast cancer cell proliferation, migration, and invasion. Mechanistically, RNA-seq, dual-luciferase reporter assay, chromatin immunoprecipitation assay, mass spectrometry, immunoprecipitation assay, and DNA pull-down assay were performed. Results: Breast cancer tissues and cells have higher STIL expression than normal tissues and cells. STIL knockdown impairs breast cancer cell growth, migration, and invasion, whereas STIL overexpression accelerates these processes. STIL promotes breast cancer progression by regulating FANCD2 expression, and exploration of its molecular mechanism demonstrated that STIL interacts with KLF16 to regulate the expression of FANCD2. Conclusions: Collectively, our findings identified STIL as a critical promoter of breast cancer progression that interacts with KLF16 to regulate Fanconi anemia pathway protein FANCD2. In summary, STIL is a potential novel biomarker and therapeutic target for breast cancer.

This paper aimed to further introduce the finite element analysis of non-smooth data for semilinear stochastic subdiffusion problems driven by fractionally integrated additive noise. The mild solution of this stochastic model consisted of three different Mittag-Leffler functions. We analyzed the smoothness of the solution and utilized complex integration to approximate the error of the solution operator under non-smooth data. Consequently, optimal convergence estimates were obtained, and we also obtained the continuity conditions of the mild solution. Finally, the influence of the fractional parameters $ \alpha $ and $ \gamma $ on the convergence rates were accurately demonstrated through numerical examples.

Abstract Effective targeting of cancer-associated fibroblasts (CAFs) is hindered by the lack of specific biomarkers and a poor understanding of the mechanisms by which different populations of CAFs contribute to cancer progression. While the role of TGFβ in CAFs is well-studied, less attention has been focused on a structurally and functionally similar protein, Activin A (encoded by INHBA). Here, we identified INHBA(+) CAFs as key players in tumor promotion and immunosuppression. Spatiotemporal analyses of patient-matched primary, metastatic, and recurrent ovarian carcinomas revealed that aggressive metastatic tumors enriched in INHBA(+) CAFs were also enriched in regulatory T cells (Tregs). In ovarian cancer mouse models, intraperitoneal injection of the Activin A neutralizing antibody attenuated tumor progression and infiltration with pro-tumorigenic subsets of myofibroblasts and macrophages. Downregulation of INHBA in human ovarian CAFs inhibited pro-tumorigenic CAF functions. Co-culture of human ovarian CAFs and T cells revealed the dependence of Treg differentiation on direct contact with INHBA(+) CAFs. Mechanistically, INHBA/recombinant Activin A in CAFs induced the autocrine expression of PD-L1 through SMAD2-dependent signaling, which promoted Treg differentiation. Collectively, our study identified an INHBA(+) subset of immunomodulatory pro-tumoral CAFs as a potential therapeutic target in advanced ovarian cancers which typically show a poor response to immunotherapy.

Abstract TNF acts as one pathogenic driver for inducing intestinal epithelial cell (IEC) death and substantial intestinal inflammation. How the IEC death is regulated to physiologically prevent intestinal inflammation needs further investigation. Here, we report that EF-hand domain-containing protein D2 (EFHD2), highly expressed in normal intestine tissues but decreased in intestinal biopsy samples of ulcerative colitis patients, protects intestinal epithelium from TNF-induced IEC apoptosis. EFHD2 inhibits TNF-induced apoptosis in primary IECs and intestinal organoids (enteroids). Mice deficient of Efhd2 in IECs exhibit excessive IEC death and exacerbated experimental colitis. Mechanistically, EFHD2 interacts with Cofilin and suppresses Cofilin phosphorylation, thus blocking TNF receptor I (TNFR1) internalization to inhibit IEC apoptosis and consequently protecting intestine from inflammation. Our findings deepen the understanding of EFHD2 as the key regulator of membrane receptor trafficking, providing insight into death receptor signals and autoinflammatory diseases.

Abstract The synovium is an important component of any synovial joint and is the major target tissue of inflammatory arthritis. However, the multi-omics landscape of synovium required for functional inference is absent from large-scale resources. Here we integrate genomics with transcriptomics and chromatin accessibility features of human synovium in up to 245 arthritic patients, to characterize the landscape of genetic regulation on gene expression and the regulatory mechanisms mediating arthritic diseases predisposition. We identify 4765 independent primary and 616 secondary cis-expression quantitative trait loci (cis-eQTLs) in the synovium and find that the eQTLs with multiple independent signals have stronger effects and heritability than single independent eQTLs. Integration of genome-wide association studies (GWASs) and eQTLs identifies 84 arthritis related genes, revealing 38 novel genes which have not been reported by previous studies using eQTL data from the GTEx project or immune cells. We further develop a method called eQTac to identify variants that could affect gene expression by affecting chromatin accessibility and identify 1517 regions with potential regulatory function of chromatin accessibility. Altogether, our study provides a comprehensive synovium multi-omics resource for arthritic diseases and gains new insights into the regulation of gene expression.

Analog quantum simulation is an essential routine for quantum computing and plays a crucial role in studying quantum many-body physics. Typically, the quantum evolution of an analog simulator is largely determined by its physical characteristics, lacking the precise control or versatility of quantum gates. This limitation poses challenges in extracting physical properties on analog quantum simulators, an essential step of quantum simulations. To address this issue, we introduce the Hamiltonian shadow protocol, which uses a single quench Hamiltonian for estimating arbitrary state properties, eliminating the need for ancillary systems and random unitaries. Additionally, we derive the sample complexity of this protocol and show that it performs comparably to the classical shadow protocol. The Hamiltonian shadow protocol does not require sophisticated control and can be applied to a wide range of analog quantum simulators. We demonstrate its utility through numerical demonstrations with Rydberg atom arrays under realistic parameter settings. The new protocol significantly broadens the application of randomized measurements for analog quantum simulators without precise control and ancillary systems.

Background: Polycystic ovary syndrome (PCOS) is characterized by excess androgens, ovulatory dysfunction, and polycystic ovaries. The mechanisms underlying ovulatory and metabolic disorders in PCOS remain elusive, hampering therapeutic development. Enhanced metabolic health correlates with increased microbiota gene content and microbial diversity. We aimed to explore the impact of gut microbiota and serum steroids on PCOS regulation associated with androgen excess.Methods: The fecal samples of patients with hyperandrogenic PCOS (n = 14) and control group with PCOS (n = 14) were analyzed by 16S rRNA gene sequencing. The peripheral venous blood of all subjects was collected to detect serum hormones. The association between gut microbiota and serum hormones was analyzed with the R language.Results: Our findings reveal that the hyperandrogenic PCOS group exhibits lower richness and diversity of gut microbiota compared to the control group. Characteristic genera in PCOS patients with hyperandrogenism include Bifidobacterium, Enterobacteriaceae_unclassified, Streptococcus, Saccharimonadaceae, Enterococcus, and Eubacterium_nodatum_group. Five hormones, including 5β-androsterone, deoxycorticosterone, corticosterone, 11-dehydrocorticosterone, and cortexolone, emerge as potential serum biomarkers for identifying patients with hyperandrogenic-PCOS (HA-PCOS). Furthermore, a lower vitamin D3 level may act as a susceptibility factor, suggesting that vitamin D3 supplementation could serve as a potential intervention for PCOS with hyperandrogenism.Conclusion: Specific fecal microbiota and serum steroids may be used as characteristic markers for clinical diagnosis of hyperandrogenic-PCOS. This research enhances our understanding of the intricate interplay among hormones, gut microbiota, and hyperandrogenemia in patients with PCOS.

Due to a dramatic increase in livestock, the impact of grazing on animal communities is a global conservation concern, especially in temperate forests. Recognizing the interaction between livestock and wildlife is essential for developing more effective and holistic strategies for wildlife conservation and sustainable livestock management. In this study, we conducted systematic camera trapping at 129 sites within the central portion of the Giant Panda National Park in China to assess the interspecific relationships between livestock and 21 sympatric wild species. Using the joint species distribution model, we fitted a null model and a constrained model to investigate the distinction between the spatial distribution relationship of species (as raw associations) and the interactions between livestock and wildlife (as residual associations). The results of raw associations showed that livestock exhibited a significant positive spatial co-occurrence with Temminck's tragopan, Himalayan porcupine, Chinese serow, Reeves's muntjac, and forest musk-deer (p 0.05), indicating no strong evidence of negative interactions between livestock and wildlife. Since livestock grazing is a source of income for residents, grazing management policies within the Giant Panda National Park should not prohibit all grazing practices.

In order to explore the application potential of aspartic protease (Asp) of Trichoderma sp., the protease gene (asp) was cloned from Trichoderma asperellum by real-time polymerase chain reaction, and was successfully expressed in Pichia Pastoris GS115. The recombinant protease (rAsp) was isolated and purified, and its biochemical properties and its effectiveness in hydrolyzing soy protein isolate (SPI) were studied. The results showed that the protease encoded by the asp gene belonged to the aspartic protease family, and its sequence identity with other members of this family was up to 47.74%. The protease activity of rAsp in the fermentation broth obtained by induced expression in a conical flask was 25.8 U/mL. The optimal reaction pH and temperature of rAsp were 2.5 and 45 ℃, respectively, and rAsp had strong stability in the pH range of 2.0–6.0 and below 45 ℃. The activity of rAsp was promoted by Cu2+ and Mn2+ but inhibited by Fe3+, sodium dodecylsulfate (SDS) and pepstantin. The hydrolysis efficiency of SPI with rAsp was 7.7% higher than that with commercial pepsin. Moreover, the ability of rAsp to reduce the allergenicity of β-conglycinin and glycinin was 1.4 and 1.8 times greater than that of the pepsin, respectively. Therefore, rAsp has potential application in soy protein processing.

Abstract Background The efficacy of anti‐programmed cell death protein 1 (PD‐1) immunotherapy in various cancers, including gastric cancer (GC), needs to be potentiated by more effective targeting to enhance therapeutic efficacy or identifying accurate biomarkers to predict clinical responses. Here, we attempted to identify molecules predicting or/and promoting anti‐PD‐1 therapeutic response in advanced GC (AGC). Methods The transcriptome of AGC tissues from patients with different clinical responses to anti‐PD‐1 immunotherapy and GC cells was analyzed by RNA sequencing. The protein and mRNA levels of the major facilitator superfamily domain containing 2A (MFSD2A) in GC cells were assessed via quantitative real‐time polymerase chain reaction, Western blotting, and immunohistochemistry. Additionally, the regulation of anti‐PD‐1 response by MFSD2A was studied in tumor‐bearing mice. Cytometry by Time‐of‐Flight, multiple immunohistochemistry, and flow cytometry assays were used to explore immunological responses. The effects of MFSD2A on lipid metabolism in mice cancer tissue and GC cells was detected by metabolomics. Results Higher expression of MFSD2A in tumor tissues of AGC patients was associated with better response to anti‐PD‐1 immunotherapy. Moreover, MFSD2A expression was lower in GC tissues compared to adjacent normal tissues, and its expression was inversely correlated with GC stage. The overexpression of MFSD2A in GC cells enhanced the efficacy of anti‐PD‐1 immunotherapy in vivo by reprogramming the tumor microenvironment (TME), characterized by increased CD8+ T cell activation and reduced its exhaustion. MFSD2A inhibited transforming growth factor β1 (TGFβ1) release from GC cells by suppressing cyclooxygenase 2 (COX2)‐prostaglandin synthesis, which consequently reprogrammed TME to promote anti‐tumor T cell activation. Conclusions MFSD2A potentially serves as a predictive biomarker for anti‐PD‐1 immunotherapy response in AGC patients. MFSD2A may be a promising therapeutic target to potentiate the efficacy of anti‐PD‐1 immunotherapy by reprogramming the TME to promote T cells activation.

Nanotechnology has ushered in significant advancements in drug design, revolutionizing the prevention, diagnosis, and treatment of various diseases. The strategic utilization of nanotechnology to enhance drug loading, delivery, and release has garnered increasing attention, leveraging the enhanced physical and chemical properties offered by these systems. Polyamidoamine (PAMAM) dendrimers have been pivotal in drug delivery, yet there is room for further enhancement. In this study, we conjugated PAMAM dendrimers with chitosan (CS) to augment cellular internalization in tumor cells. Specifically, doxorubicin (DOX) was initially loaded into PAMAM dendrimers to form DOX-loaded PAMAM (DOX@PAMAM) complexes via intermolecular forces. Subsequently, CS was linked onto the DOX-loaded PAMAM dendrimers to yield CS-conjugated PAMAM loaded with DOX (DOX@CS@PAMAM) through glutaraldehyde crosslinking via the Schiff base reaction. The resultant DOX@CS@PAMAM complexes were comprehensively characterized using Fourier-transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS). Notably, while the drug release profile of DOX@CS@PAMAM in acidic environments was inferior to that of DOX@PAMAM, DOX@CS@PAMAM demonstrated effective acid-responsive drug release, with a cumulative release of 70% within 25 h attributed to the imine linkage. Most importantly, DOX@CS@PAMAM exhibited significant selective cellular internalization rates and antitumor efficacy compared to DOX@PAMAM, as validated through cell viability assays, fluorescence imaging, and flow cytometry analysis. In summary, DOX@CS@PAMAM demonstrated superior antitumor effects compared to unconjugated PAMAM dendrimers, thereby broadening the scope of dendrimer-based nanomedicines with enhanced therapeutic efficacy and promising applications in cancer therapy.

We introduce a quantum information theory-inspired method to improve the characterization of many-body Hamiltonians on near-term quantum devices. We design a new class of similarity transformations that, when applied as a preprocessing step, can substantially simplify a Hamiltonian for subsequent analysis on quantum hardware. By design, these transformations can be identified and applied efficiently using purely classical resources. In practice, these transformations allow us to shorten requisite physical circuit-depths, overcoming constraints imposed by imperfect near-term hardware. Importantly, the quality of our transformations is $tunable$: we define a 'ladder' of transformations that yields increasingly simple Hamiltonians at the cost of more classical computation. Using quantum chemistry as a benchmark application, we demonstrate that our protocol leads to significant performance improvements for zero and finite temperature free energy calculations on both digital and analog quantum hardware. Specifically, our energy estimates not only outperform traditional Hartree-Fock solutions, but this performance gap also consistently widens as we tune up the quality of our transformations. In short, our quantum information-based approach opens promising new pathways to realizing useful and feasible quantum chemistry algorithms on near-term hardware.

Abstract Background To develop and validate a multivariable risk prediction model for ketosis‐prone type 2 diabetes mellitus (T2DM) based on clinical characteristics. Methods A total of 964 participants newly diagnosed with T2DM were enrolled in the modeling and validation cohort. Baseline clinical data were collected and analyzed. Multivariable logistic regression analysis was performed to select independent risk factors, develop the prediction model, and construct the nomogram. The model's reliability and validity were checked using the receiver operating characteristic curve and the calibration curve. Results A high morbidity of ketosis‐prone T2DM was observed (20.2%), who presented as lower age and fasting C‐peptide, and higher free fatty acids, glycated hemoglobin A1c and urinary protein. Based on these five independent influence factors, we developed a risk prediction model for ketosis‐prone T2DM and constructed the nomogram. Areas under the curve of the modeling and validation cohorts were 0.806 (95% confidence interval [CI]: 0.760–0.851) and 0.856 (95% CI: 0.803–0.908). The calibration curves that were both internally and externally checked indicated that the projected results were reasonably close to the actual values. Conclusions Our study provided an effective clinical risk prediction model for ketosis‐prone T2DM, which could help for precise classification and management.

Abstracts Phosphorylation of IRF3 is critical to induce type I interferon (IFN-I) production in antiviral innate response. Here we report that lysine methyltransferase SMYD2 inhibits the expressions of IFN-I and proinflammatory cytokines in macrophages upon viral infections. The Smyd2-deficient mice are more resistant to viral infection by producing more IFN-I and proinflammatory cytokines. Mechanistically, SMYD2 inhibits IRF3 phosphorylation in macrophages in response to viral infection independent of its methyltransferase activity. We found that SMYD2 interacts with the DNA-binding domain (DBD) and IRF association domain (IAD) domains of IRF3 by its insertion SET domain (SETi) and could recruit phosphatase PP1α to enhance its interaction with IRF3, which leads to decreased phosphorylation of IRF3 in the antiviral innate response. Our study identifies SMYD2 as a negative regulator of IFN-I production against virus infection. The new way of regulating IRF3 phosphorylation will provide insight into the understanding of IFN-I production in the innate response and possible intervention of the related immune disorders.

Abstract Introduction The mortality rate of hospitalized patients with severe hospital-acquired pneumonia (SHAP) remains high. Empirical broad-spectrum antibiotic coverage and the misuse of high-grade antibiotics could lead to the emergence of multi-drug and even pandrug-resistant bacteria. In addition to metagenomic next-generation sequencing (mNGS), microbiological rapid on-site evaluation (M-ROSE) might be a useful technique to identify the pathogens in the early stage; however, the effect of M-ROSE guiding anti-infection treatment on prognostic outcomes of SHAP patients is still unclear. Methods/design This is a multicenter, single-blind, prospective, randomized controlled trial to evaluate the effect of M-ROSE guiding anti-infection treatment in SHAP patients, which will provide new strategies for the prevention and control of clinical multi-drug resistance bacteria. A total of 166 patients with SHAP, aged 18 years and over, will be recruited from seven centers in Beijing and randomly assigned to the intervention group (M-ROSE combined with mNGS) or the control group (mNGS only) in a 1:1 ratio using the central randomization system. Patients in the intervention group will accept M-ROSE and mNGS analysis, and the control group will accept mNGS analysis. Individualized anti-infective treatment and routine treatment will be selected according to the analysis results. The primary outcome is the ICU outcome (mortality). The safety of the intervention measures will be evaluated during the entire trial period. This trial will be the first randomized controlled trial to evaluate the effect of M-ROSE guiding treatment on mortality in patients with SHAP and may change the prevalence of multi-drug resistant bacteria. Ethics and dissemination This trial adheres to the Declaration of Helsinki and guidelines of Good Clinical Practice. Signed informed consent will be obtained from all participants. The trial has been approved by the Chinese PLA General Hospital (Approval Number: 20220322001). Trial registration ClinicalTrials.gov NCT05300776. Registered on 25 March 2022.

This study aimed to explore the efficacy and potential mechanisms of rechallenge therapy with microtubule-targeting agents (MTAs) in patients with HER2-low metastatic breast cancer (MBC). We performed a systematic review to investigate the rechallenge treatment concept in the field of HER2-low MBC treatment and utilized a series of cases identified in the literature to illustrate the concept. Here we reported two clinical cases of HER2-low MBC patients whose disease progressed after prior treatment with MTAs such as docetaxel and vincristine. When rechallenged with disitamab vedotin ((RC48-antibody-drug conjugate (ADC), a monomethyl auristatin (MMAE) MTA)), both patients achieved a partial response and the final progression-free survival (PFS) was 13.5 and 9 months, respectively. Genomic profiling detected a PIK3CA H1047R mutation in the patients. The patients were treated with everolimus before being rechallenged with RC48, which may lead to a better response. This study further summarizes and analyzes the potential mechanism of the PI3K-AKT signaling pathway in MTA resistance and reveals that the PIK3CA H1047R mutation may be a potential molecular marker for the efficacy prediction of mTOR inhibitors, providing new insights and potential therapeutic strategies for the application of MTAs to MBC patients.

Abstract Background Visceral obesity is associated with high cardiovascular events risk in type 2 diabetes mellitus (T2DM). Whether normal-weight visceral obesity will pose a higher atherosclerotic cardiovascular disease (ASCVD) risk than body mass index (BMI)-defined overweight or obese counterparts with or without visceral obesity remains unclear. We aimed to explore the relationship between general obesity and visceral obesity and 10-year ASCVD risk in patients with T2DM. Methods Patients with T2DM (6997) who satisfied the requirements for inclusion were enrolled. Patients were considered to have normal weight when 18.5 kg/m2 ≤ BMI

ABSTRACTIt is critical to determine the real-world performance of vaccines against coronavirus disease 2019 (COVID-19) so that appropriate treatments and policies can be implemented. There was a rapid wave of infections by the Omicron variant in Jilin Province (China) during spring 2022. We examined the effectiveness of inactivated vaccines against Omicron using real-world data from this epidemic. This retrospective case-case study of vaccine effectiveness (VE) examined infected patients who were quarantined and treated from April 16 to June 8, 2022 and responded to an electronic questionnaire. Data were analyzed by univariable and multivariable analyses. A total of 2968 cases with SARS-CoV-2 infections (asymptomatic: 1061, mild disease: 1763, pneumonia: 126, severe disease: 18) were enrolled in the study. Multivariable regression indicated that the risk for pneumonia or severe disease was greater in those who were older or had underlying diseases, but was less in those who received COVID-19 vaccines. Relative to no vaccination, VE against the composite of pneumonia and severe disease was significant for those who received 2 doses (60.1%, 95%CI: 40.0%, 73.5%) or 3 doses (68.1%, 95%CI: 44.6%, 81.7%), and VE was similar in the subgroups of males and females. However, VE against the composite of all three classes of symptomatic diseases was not significant overall, nor after stratification by sex. There was no statistical difference in the VE of vaccines from different manufacturers. The inactivated COVID-19 vaccines protected patients against pneumonia and severe disease from Omicron infection, and booster vaccination enhanced this effect.

Summary: The roles of long noncoding RNA (lncRNA) and RNA-binding proteins (RBPs) in antiviral innate response warrant further investigation. Here, we identify an lncRNA, termed lncRNA-BTX (between Tbk1 and Xpot), which is upregulated upon viral infection via an IRF3-type I interferon-independent pathway, promoting viral innate immune escape. Deletion of lncRNA-BTX in cells or mice significantly reduces viral load in vitro or in vivo, respectively. Mechanistically, lncRNA-BTX strengthens the interactions between DHX9 or ILF3 (two RBPs that have opposite functions in regulating the replication of RNA virus) and their respective partner, JMJD6 or ILF2, which regulates intracellular translocations of DHX9 and ILF3 from the nucleus to the cytoplasm. Put simply, lncRNA-BTX facilitates DHX9’s return to the cytoplasm and retains ILF3 within the nucleus, promoting viral replication. This work unveils a strategy developed by the virus to bypass host innate immunity, thus providing a potential target for antiviral therapeutics.

Objective To establish a monitoring system and a standard database system for neonatal hearing screening program and evaluate its effect. Methods The hearing screening data of newborns in Nanjing in 2021 from the neonatal hearing screening information system of Jiangsu Province were selected as the experimental group, and the manual registration data of neonatal hearing screening in Nanjing in 2020 were selected as the control group. The initial screening rate, re-screening rate, referral rate and hearing impairment disease management rate of neonates were compared between two groups. Results The initial screening rate, re-screening rate and referral rate of neonatal hearing screening in the information management system were 99.27%,85.73% and 91.60% respectively, which were significantly higher than those in the manual registration control group (96.94%, 68.36% and 66.20%, P

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. NAFLD starts with hepatic lipid accumulation, which may cause inflammation and ultimately lead to fibrosis in the liver. Studies have shown that intestinal microorganisms and a variety of bioactive substances produced by them interact with host hepatocytes through the portal vein, resulting in the occurrence and development of NAFLD. The bidirectional communication between the intestinal tract and the liver is called the gut-liver axis. In this paper, the mechanism of the occurrence and development of NAFLD mediated by the gut-liver axis is elaborated from the perspectives of intestinal microbial composition, intestinal barrier function, intestinal microbial components and intestinal microbial metabolites, as well as the role of nutritional intervention in ameliorating NAFLD by targeting the gut-liver axis. This article reviews the existing knowledge on the mechanisms of the complex interaction between intestinal disorders and NAFLD in order to provide nutritional strategies for the prevention and improvement of NAFLD.

Abstract SARS-CoV-2 Omicron variant infection generally gives rise to asymptomatic to moderate COVID-19 in vaccinated people. The immune cells can be reprogrammed or “imprinted” by vaccination and infections to generate protective immunity against subsequent challenges. Considering the immune imprint in Omicron infection is unclear, here we delineate the innate immune landscape of human Omicron infection via single-cell RNA sequencing, surface proteome profiling, and plasma cytokine quantification. We found that monocyte responses predominated in immune imprints of Omicron convalescents, with IL-1β-associated and interferon (IFN)-responsive signatures with mild and moderate symptoms, respectively. Low-density neutrophils increased and exhibited IL-1β-associated and IFN-responsive signatures similarly. Mild convalescents had increased blood IL-1β, CCL4, IL-9 levels and PI3 + neutrophils, indicating a bias to IL-1β responsiveness, while moderate convalescents had increased blood CXCL10 and IFN-responsive monocytes, suggesting durative IFN responses. Therefore, IL-1β- or IFN-responsiveness of myeloid cells may indicate the disease severity of Omicron infection and mediate post-COVID conditions.

Abstract Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common life-threatening lung diseases associated with acute and severe inflammation. Both have high mortality rates, and despite decades of research on clinical ALI/ARDS, there are no effective therapeutic strategies. Disruption of alveolar-capillary barrier integrity or activation of inflammatory responses leads to lung inflammation and injury. Recently, studies on the role of extracellular vesicles (EVs) in regulating normal and pathophysiologic cell activities, including inflammation and injury responses, have attracted attention. Injured and dysfunctional cells often secrete EVs into serum or bronchoalveolar lavage fluid with altered cargoes, which can be used to diagnose and predict the development of ALI/ARDS. EVs secreted by mesenchymal stem cells can also attenuate inflammatory reactions associated with cell dysfunction and injury to preserve or restore cell function, and thereby promote cell proliferation and tissue regeneration. This review focuses on the roles of EVs in the pathogenesis of pulmonary inflammation, particularly ALI/ARDS.

Abstract Human mesenchymal stem cells (hMSCs) can be differentiated into osteoblasts and adipocytes. During these processes, super enhancers (SEs) play important roles. Here, we performed comprehensive characterization of the SEs changes associated with adipogenic and osteogenic differentiation of hMSCs, and revealed that SEs changed more dramatically compared with typical enhancers. We identified a set of lineage-selective SEs, whose target genes were enriched with cell type-specific functions. Functional experiments in lineage-selective SEs demonstrated their specific roles in directed differentiation of hMSCs. We also found that some key transcription factors regulated by lineage-selective SEs could form core regulatory circuitry (CRC) to regulate each other’s expression and control the hMSCs fate determination. In addition, we found that GWAS SNPs of osteoporosis and obesity were significantly enriched in osteoblasts-selective SEs or adipocytes-selective SEs, respectively. Taken together, our studies unveiled important roles of lineage-selective SEs in hMSCs differentiation into osteoblasts and adipocytes.

BackgroundVitamin D deficiency during pregnancy is common, but whether maternal vitamin D status affects glycolipid metabolism of offspring remains unclear.ObjectiveTo evaluate the effect of maternal vitamin D deficiency during pregnancy on the glycolipid metabolism of offspring at different life-cycles (from birth to adulthood) and to explore the improvement of different dosages of vitamin D supplementation.MethodsSprague–Dawley rats were fed vitamin D-deprived (VDD group) or standard vitamin D diets (SC group) during pregnancy, and their diets were changed to standard vitamin D diets during lactation (the offspring were sorted into VDDoffspring and SCoffspring groups). After weaning, rats in the VDDoffspring group were randomly assigned to the VDDoffspring, VDDoffspring-S3300 and VDDoffspring-S10000 groups with diets containing standard, medium and high dosages of vitamin D for 12 wk. Serum was collected for biochemical analyses at postnatal Day 21, postnatal Day 56 and postnatal Day 84. Oral glucose tolerance test (OGTT) was performed at postnatal Day 70.ResultsCompared to SCoffspring, rats in the VDDoffspring group had significantly lower birth weight with faster weight gain and higher levels of lipid metabolism in early life. After near adulthood, the differences in weight and lipid metabolism between the two groups disappeared. OGTT showed significantly higher blood glucose levels in the VDDoffspring group at 30 min, 60 min, and 90 min. The continuation of vitamin D supplementation at medium and high dosages after weaning did not cause any obvious changes in weight or glycolipid metabolism (except for postprandial hyperglycemia). OGTT demonstrated that the glucose levels in the VDDoffspring-S3300 group were lowest at all the time points and that those in the VDDoffspring-S10000 group were the highest at 30 min, 60 min, and 90 min among the three groups.ConclusionThe adverse effects of vitamin D deficiency during pregnancy on glycolipid metabolism in offspring vary in different stages. Over a long time period, adequate vitamin D supplementation is beneficial to glycolipid metabolism for the offspring of subjects with vitamin D deficiency during pregnancy; however, further improvement is required.

We develop a strong coupling approach towards quantum magnetism in Mott insulators for Wannier-obstructed bands. Despite the lack of Wannier orbitals, electrons can still singly occupy a set of exponentially localized but nonorthogonal orbitals to minimize the repulsive interaction energy. We develop a systematic method to establish an effective spin model from the electron Hamiltonian using a diagrammatic approach. The nonorthogonality of the Mott basis gives rise to multiple new channels of spin-exchange (or permutation) interactions beyond Hartree–Fock and superexchange terms. We apply this approach to a Kagome lattice model of interacting electrons in Wannier-obstructed bands (including both Chern bands and fragile topological bands). Due to the orbital nonorthogonality, as parameterized by the nearest-neighbor orbital overlap g, this model exhibits stable ferromagnetism up to a finite bandwidth W∼Ug, where U is the interaction strength. This provides an explanation for the experimentally observed robust ferromagnetism in Wannier-obstructed bands. The effective spin model constructed through our approach also opens up the possibility for frustrated quantum magnetism around the ferromagnet-antiferromagnet crossover in Wannier-obstructed bands.

Abstract Snow nitrate is vulnerable to photolytic loss that causes isotopic alteration, and thus its isotopes can potentially track the extent of snow nitrate photolysis and its impacts in environments where loss is significant. Large increases in δ15N‐NO3− below the snow surface have been attributed to photolysis and this behavior is generally consistent amongst theoretical as well as lab and field studies. Oxygen isotope ratios are thought to be influenced by photolysis as well as secondary condensed‐phase chemistry, but the competing effects have yet to be reconciled. Here we use a model that simulates nitrate burial, photolytic fractionation, and re‐oxidation in snow to quantitatively assess these processes with the aim of developing a consistent framework for interpreting the photolytic effects of the complete nitrate isotopic composition (δ15N, δ18O, and Δ17O). This study reveals that isotopic effects of nitrate photolysis and aqueous‐phase re‐oxidation chemistry are important sources of uncertainties in modeling δ18O‐NO3−.

The paper explores strategies to enhance the energy storage efficiency (η) of relaxor- ferroelectric (RFE) ceramics by tailoring the structural parameter tolerance factor (t), which indicates the stability of a perovskite. KTaO3 (KT) with a t of 1.054 has been selected to modulate the t value of 0.75Bi0.5Na0.5TiO3-0.25BaTiO3 (BNT-BT, t = 0.9967), and a serials of (1 − x)(BNT-BT)-xKT (x = 0–0.10) RFE ceramics with t from 0.997 to 1.003 have been prepared. Structural analyses show that all the ceramics possess typical perovskite structure, and the average grain size decrease with the addition of KT. The tested dielectric characteristics present that with the increase of t to 1, the diffuse-phase-transition peak is gradually diminished in the dielectric constant vs temperature (εr-T) curves, while the relaxation-dielectric behavior is gradually strengthened, and the temperature stability of the dielectric constant is improved. The breakdown strength is also enlarged with the increase of KT content. As a result, the 0.94(BNT-BT)-0.06KT with t = 1.0004, which is closest to 1, achieving a recoverable energy storage density (Wrec) of 4.9 J/cm3 and η of 91.8% at 336 kV/cm, which are 191.7% and 49.5% higher than the Wrec (1.68 J/cm3) and η (61.4%) of pure 0.75BNT-0.25BT ceramic, respectively. These findings offer a promising approach for enhance the energy storage properties of RFE ceramics. [ABSTRACT FROM AUTHOR]

In order to meet the demand of cadmium substitution for civil aircraft, the differences of galvanized nickel process requirements in Boeing, Airbus, Bombardier and other famous aircraft manufacturer were analyzed, and the NZ - 70 series alkaline galvanized nickel solution electroplating samples widely used in China were tested. Results showed that NZ - 70 galvanized nickel solution could meet the enterprise requirements of Boeing, Airbus, Bombardier, and American aerospace material specifications for galvanized nickel adhesion, corrosion resistance, nickel content, hydrogen embrittlement. In addition, the hydrogen leakage of the coating was not lower than the performance requirements of cyanide cadmium and titanium plating, which could replace the imported solution for the surface protection of high - strength steel parts of civil aircraft.

Introduction: Tumors are usually refractory to anti-cancer therapeutics under hypoxic conditions. However, the underlying molecular mechanism remains to be elucidated. Objectives: Our study intended to identify hypoxia inducible lncRNAs and their biological function in gastric cancer (GC). Methods: Differentially expressed lncRNAs were determined by microarray analysis between GC cells exposed to hypoxia (1% O2) and normoxia (21% O2) for 24 h. The expression level of CBSLR was manipulated in several GC cell lines to perform molecular and biological analyses both in vitro and in vivo. Results: We identified a hypoxia-induced lncRNA-CBSLR that protected GC cells from ferroptosis, leading to chem-resistance. Mechanically, CBSLR interacted with YTHDF2 to form a CBSLR/YTHDF2/CBS signaling axis that decreased the stability of CBS mRNA by enhancing the binding of YTHDF2 with the m6A-modified coding sequence (CDS) of CBS mRNA. Furthermore, under decreased CBS levels, the methylation of the ACSL4 protein was reduced, leading to protein polyubiquitination and degradation of ACSL4. This, in turn, decreased the pro-ferroptosis phosphatidylethanolamine (PE) (18:0/20:4) and PE (18:0/22:4) content and contributed to ferroptosis resistance. Notably, CBSLR is upregulated, whereas CBS is downregulated in GC tissues compared to matched normal tissues; and GC patients with high CBSLR/low CBS levels have a worse clinical outcome and a poorer response to chemotherapy. Conclusion: Our study reveals a novel mechanism in how HIF1α/CBSLR modulates ferroptosis/chemoresistance in GC, illuminating potential therapeutic targets for refractory hypoxic tumors.

Abstract Backgroud Multiple myeloma (MM) is an incurable plasma cell malignancy in the bone marrow (BM), while immunoglobulin D type of MM (IgD MM) is a very rare but most severe subtype in all MM cases. Therefore, systemic study on IgD MM is purposeful to disclose the recurrent and refractory features in both IgD and other types of MM, and beneficial to the development of potent therapeutic strategy on MM. Methods Agilent SBC-ceRNA microarray chips were employed to examine 3 normal plasma cell samples (NPCs), 5 lgD MM samples and 5 lgG MM samples, respectively. Sanger sequencing, RNase R digestion and qPCR assays were used to detect the existence and expression of circHNRNPU. BaseScope™ RNA ISH assay was performed to test circHNRNPU levels in paraffin-embedded MM tissues. The protein encoded by circHNRNPU was identified by LC-MS/MS, which was named as circHNRNPU_603aa. The function of circHNRNPU_603aa on cellular proliferation and cell cycle was assessed by MTT test, colony formation assay, flow cytometry and MM xenograft mouse model in vivo. RIP-seq, RIP-PCR and WB analysis for ubiquitination were performed to explore the potential mechanism of circHNRNPU_603aa in MM. Exosomes were isolated from the culture supernatant of MM cells by ultracentrifugation and characterized by Transmission Electron Microscope and WB confirmation of exosomes markers Alix and CD9. Results CircHNRNPU was one of the top most abundant and differentially expressed circRNA in IgD MM relative to lgG and NPCs samples. Increased circHNRNPU was associated with poor outcomes in four independent MM patient cohorts. Intriguingly, MM cells secreted circHNRNPU, which encoded a protein named as circHNRNPU_603aa. Overexpressed circHNRNPU_603aa promoted MM cell proliferation in vitro and in vivo, in contrast knockdown of circHNRNPU_603aa by siRNA abrogated these effects. Due to circHNRNPU_603aa including RNA-binding RGG-box region, it regulated SKP2 exon skipping, thereby competitively inhibited c-Myc ubiquitin so as to stabilize c-Myc in MM. MM cells secreted circHNRNPU through exosomes to interfere with various cells in the BM microenvironment. Conclusion Our findings demonstrate that circHNRNPU_603aa is a promising diagnostic and therapeutic marker in both MM cells and BM niche.

The study aimed to screen out the compound natural preservative suitable for Sauropus androgynus(L.) Merr.. In this experiment, the Hainan Sauropus androgynus(L.) Merr. was as experiment material, and three natural preservatives were investigated by L9(34) orthogonal test based on single factor experiment. The effects of chitosan, tea tree oil nanoemulsion and tea saponin solution on chlorophyll content, VC content, sensory quality and weight loss rate of Sauropus androgynus(L.) Merr. during storage were investigated. Then the distilled water treatment group was used as the control, the preservation effect was compared between the natural preservative and the traditional chemical preservative(chlorine dioxide). The results showed that the optimal compound preservative formula was tea saponin 2 mg/mL, tea tree oil nanoemulsion 4 mg/mL and chitosan solution 15 mg/mL. With this formula, the contents of chlorophyll and VC lost less, and the weight loss rate was low, and the sensory quality of Sauropus androgynus(L.) Merr. could be maintained well after 6 days storage. The comprehensive score of preservation effect was 86.05. The preservation effects of the compound natural preservative and the chemical preservative were better than that of the control group, and the preservation effect of compound natural preservative was slightly better than that of traditional chemical preservative, especially in maintaining chlorophyll content and reducing weight loss. The compound natural preservative selected in this experiment has a good effect on the preservation of Sauropus androgynus(L.) Merr.. And it has great application prospect as the green preservative of Sauropus androgynus(L.) Merr..

Abstract Background In sepsis, vitamin D binding protein (VDBP) has been shown to be low-expressed. The current study examined the relationship between serum VDBP level and liver injury in sepsis patients, as well as in a mouse model for sepsis and in cultured liver epithelial cell line exposed to lipopolysaccharide (LPS). Methods The human study included 78 sepsis patients and 50 healthy volunteers. Sepsis patients were categorized into sepsis survivor group (n = 43) and sepsis non-survivor group (n = 35) based on 28-day mortality for data analysis. Adult male C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Serum samples were collected on day 1, 3, 5 and 7 to determine the levels of VDBP, 25-hydroxyvitamin D [25(OH)D3], 1,25-dihydroxyvitamin D [1,25(OH)2D3], interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Potential protective effects of VDBP overexpression against LPS-induced liver damage were examined in cultured THLE2 cells. Results Serum levels of VDBP, 25(OH)D3, and 1,25(OH)2D3 were significantly lower in sepsis patients vs. the healthy control (P

Abstract Phylogenetic analysis has entered the genomics (multilocus) era. For less experienced researchers, conquering the large number of software programs required for a multilocus‐based phylogenetic reconstruction can be somewhat daunting and time‐consuming. PhyloSuite, a software with a user‐friendly GUI, was designed to make this process more accessible by integrating multiple software programs needed for multilocus and single‐gene phylogenies and further streamlining the whole process. In this protocol, we aim to explain how to conduct each step of the phylogenetic pipeline and tree‐based analyses in PhyloSuite. We also present a new version of PhyloSuite (v1.2.3), wherein we fixed some bugs, made some optimizations, and introduced some new functions, including a number of tree‐based analyses, such as signal‐to‐noise calculation, saturation analysis, spurious species identification, and etc. The step‐by‐step protocol includes background information (i.e., what the step does), reasons (i.e., why do the step), and operations (i.e., how to do it). This protocol will help researchers quick‐start their way through the multilocus phylogenetic analysis, especially those interested in conducting organelle‐based analyses.

Abstract Extracellular vesicles (EVs) have emerged as important vectors of intercellular dialogue. High mobility group box protein 1 (HMGB1) is a typical damage-associated molecular pattern (DAMP) molecule, which is cytotoxic and leads to cell death and tissue injury. Whether EVs are involved in the release of HMGB1 in lipopolysaccharide (LPS)-induced acute liver injuries need more investigation. EVs were identified by transmission electron microscopy, nanoparticle tracking analysis (NTA), and western blotting. The co-localization of HMGB1, RAGE (receptor for advanced glycation end-products), EEA1, Rab5, Rab7, Lamp1 and transferrin were detected by confocal microscopy. The interaction of HMGB1 and RAGE were investigated by co-immunoprecipitation. EVs were labeled with the PKH67 and used for uptake experiments. The pyroptotic cell death was determined by FLICA 660-YVAD-FMK. The expression of NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasomes were analyzed by western-blot or immunohistochemistry. Serum HMGB1, ALT (alanine aminotransferase), AST (aspartate aminotransferase), LDH (lactate dehydrogenase) and MPO (myeloperoxidase) were measured using a commercial kit. The extracellular vesicle HMGB1 was detected in the serums of sepsis patients. Macrophages were found to contribute to HMGB1 release through the EVs. HMGB1-RAGE interactions participated in the loading of HMGB1 into the EVs. These EVs shuttled HMGB1 to target cells by transferrin-mediated endocytosis leading to hepatocyte pyroptosis by the activation of NLRP3 inflammasomes. Moreover, a positive correlation was verified between the sepsis serum EVs-HMGB1 level and clinical liver damage. This finding provides insights for the development of novel diagnostic and therapeutic strategies for acute liver injuries.

Abstract Transmembrane protein (TMEM) is a family of protein that spans cytoplasmic membranes and allows cell–cell and cell–environment communication. Dysregulation of TMEMs has been observed in multiple cancers. However, little is known about TMEM116 in cancer development. In this study, we demonstrate that TMEM116 is highly expressed in non-small-cell lung cancer (NSCLC) tissues and cell lines. Inactivation of TMEM116 reduced cell proliferation, migration and invasiveness of human cancer cells and suppressed A549 induced tumor metastasis in mouse lungs. In addition, TMEM116 deficiency inhibited PDK1-AKT-FOXO3A signaling pathway, resulting in accumulation of TAp63, while activation of PDK1 largely reversed the TMEM116 deficiency induced defects in cancer cell motility, migration and invasive. Together, these results demonstrate that TMEM116 is a critical integrator of oncogenic signaling in cancer metastasis.

SINOPEC has made significant progress in natural gas exploration in terrigenous tight sandstone in the Western Sichuan Depression, making it one of the predominant exploration areas in the Sichuan Basin. Although the Chengdu large gas field was located in the main reservoirs of Upper Jurassic tight sandstone, few geochemical proofs were presented to support the explanation of the gas source, and regional differences in natural gas have been poorly investigated. The Jurassic tight gas in the Chengdu large gas field has a dryness coefficient (C1/C1-5) of 0.939–0.982, and the δ13C1, δ13C2, and δD1 values range from −33.7‰ to −30.7‰, −25.4‰ to −22.3‰, and −162‰ to −153‰, respectively, with positive carbon and hydrogen isotopic series of gaseous alkanes. The carbon and hydrogen isotopic compositions of the Jurassic tight gas indicate that it is typically coal-derived gas. The measured vitrinite reflectance (RO) values of source rocks of Member 5 of the Xujiahe Formation, which are demonstrated as the main source of Jurassic tight gas, are consistent with the calculated RO values according to the two-stage fractionation model of coal-derived gas. Effective source rocks are rare in the Lower Jurassic Baitianba Formation of the study area, which is considered to have only a minor contribution to the Jurassic gas reservoirs. The geochemical characteristics of Jurassic natural gas from various gas fields in the Western Sichuan Depression vary depending on the effect of different gas sources and accumulation processes.