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The purpose of the article is to investigate Dirichlet boundary-value problems of the fractional $ p $-Laplacian equation with impulsive effects. By using the Nehari manifold method, mountain pass theorem and three critical points theorem, some new results are achieved under more general growth conditions. In addition, this paper weakens the commonly used $ p $-suplinear and $ p $-sublinear growth conditions.

Background Checkpoint-based immunotherapy has failed to elicit responses in the majority of patients with pancreatic cancer. In our study, we aimed to identify the role of a novel immune checkpoint molecule V-set Ig domain-containing 4 (VSIG4) in pancreatic ductal adenocarcinoma (PDAC). Methods Online datasets and tissue microarray (TMA) were utilized to analyze the expression level of VSIG4 and its correlation with clinical parameters in PDAC. CCK8, transwell assay and wound healing assay were applied to explore the function of VSIG4 in vitro. Subcutaneous, orthotopic xenograft and liver metastasis model was established to explore the function of VSIG4 in vivo. TMA analysis and chemotaxis assay were conducted to uncover the effect of VSIG4 on immune infiltration. Histone acetyltransferase (HAT) inhibitors and si-RNA were applied to investigate factors that regulate the expression of VSIG4. Results Both mRNA and protein levels of VSIG4 were higher in PDAC than normal pancreas in TCGA, GEO, HPA datasets and our TMA. VSIG4 showed positive correlations with tumor size, T classification and liver metastasis. Patients with higher VSIG4 expression were related to poorer prognosis. VSIG4 knockdown impaired the proliferation and migration ability of pancreatic cancer cells both in vitro and in vivo. Bioinformatics study showed positive correlation between VSIG4 and infiltration of neutrophil and tumor-associated macrophages (TAMs) in PDAC, and it inhibited the secretion of cytokines. According to our TMA panel, high expression of VSIG4 was correlated with fewer infiltration of CD8+ T cells. Chemotaxis assay also showed knockdown of VSIG4 increased the recruitment of total T cells and CD8+ T cells. HAT inhibitors and knockdown of STAT1 led to decreased expression of VSIG4. Conclusions Our data indicate that VSIG4 contributes to cell proliferation, migration and resistance to immune attack, thus identified as a promising target for PDAC treatment with good prognostic value.

Background Few studies have investigated psychogenic sexual dysfunction including psychogenic erectile dysfunction (pED); the effect of tadalafil on sexual behavior of male rats induced by chronic unpredictable mild stress (CUMS) remains unclear. Aim The aim was to explore the influence of CUMS on sexual behavior of male rats and the effects of tadalafil on that. Methods Adult male rats were divided into 3 groups, including the normal group without CUMS, the model group with 6 weeks’ CUMS, and the tadalafil group with treatment of tadalafil during CUMS. CUMS consists of water deprivation, food deprivation, stroboscopic lightning, white noise, cage tilting, weeding packing, and housing 2 unfamiliar rats. The apomorphine test and vaginal smear test were conducted with the aim to screen out male rats with good erectile function and make preparation for the sexual behavior test, respectively. Outcomes At the end of the study period, the level of anhedonia and sexual function were evaluated by the sucrose preference test, sexual behavior test, and measurement of serum testosterone, dopamine, and 5-HT. Results Sucrose preference showed significant decrease in rats after CUMS. The intromission ratio and total intromission frequency decreased significantly, while the mount latency and ejaculation latency prolonged significantly in CUMS-induced rats when compared with normal rats. Meanwhile, the treatment of tadalafil reversed the level of anhedonia and sexual function in CUMS-induced rats. However, there were no statistical differences in the levels of serum testosterone, dopamine, and 5-HT among groups. Clinical Implications The study constructed an animal model that can provide clinical insights into the mechanism of psychogenic sexual dysfunction and supports the application of tadalafil in pED therapy. Strengths and Limitations We found that CUMS-induced rats exhibited anhedonia and poor sexual function that could be prevented by tadalafil administration. Future research needs to construct the standard of pED model and explore the mechanism of tadalafil on central nervous system. Conclusion Tadalafil could prevent the changes of depression and poor sexual function in rats induced by CUMS, and the method of CUMS and the sexual behavior test should be used in the future for pED modeling.

Background Although transcription factor homeobox A10 (HOXA10) plays an important role in regulating the development of the pancreas, a pathway of HOXA10 participates in pancreatic ductal adenocarcinoma (PDAC) progression has not been revealed. Methods Immunohistochemistry assays were applied to demonstrate the relationship between HOXA10 expression and PDAC progression. Functional assays were used to illustrate the oncogenic role of HOXA10 in PDAC progression. Regulatory mechanisms of HOXA10 induced IKKβ gene transcription and the nuclear transcription factor kappa B (NF-κB) signal pathways activation were also investigated in PDAC cells. Results In the current study, we show that HOXA10 expression increased in PDAC with higher tumor stage and poor patient survival in public RNA-seq data suggesting HOXA10 is associated with PDAC progression. HOXA10 promotes PDAC cell proliferation, anchorage colony formation, and xenograft growth by activating canonical NF-κB signaling both in vitro and in vivo. Mechanically, HOXA10 up-regulates IKKβ gene transcription directly and subsequently sustain the activation of NF-κB independent of tumor necrosis factor-alpha in PDAC cells. Conclusion Collectively, up-regulation of HOXA10 gene expression promote cell growth and tumor progression through directly activating canonical NF-κB signaling in PDAC.

Pancreatic cancer, of which pancreatic ductal adenocarcinoma (PDAC) is one of the most prevalent type, is one of the most malignant tumors, with a 5-year survival rate of about 10%. Pancreatic cancer stem cells play pivotal roles in chemoresistance and recurrence. Long non-coding RNAs (lncRNAs) have been identified as key regulators of the biological progression of various cancers. Recently, lncRNAs were found to be associated with cancer stem cells, which are related to chemoresistance. LINC01137 was predicted associated with pancreatic cancer stem cells, however, its function and underlying mechanisms in pancreatic cancer remain unclear. In this study, we found that LINC01137 was upregulated in pancreatic cancer tissues and cell lines. Its high expression correlated with advanced pathological stages and poor prognosis. Induction of LINC01137 expression boosted pancreatic cancer stemness, chemoresistance, and proliferation. Mechanistically, LINC01137 exerted its biological function by binding to miR-7155-5p to activate the KLF12/PI3K/AKT pathway. KLF12 also promoted LINC01137 expression. LINC01137 and KLF12 were involved in promoting PDAC tumorigenesis. Our results suggested that LINC01137 functions as an oncogene in pancreatic cancer and identified its post-transcriptional regulatory mechanisms, which may contribute to targeted therapy for pancreatic cancer.

Green housing reduces resource consumption and protects the ecological environment. Sustainable buildings and construction have gained increasing attention in the last decade. Many empirical studies have confirmed that green housing imposes a price premium at the presale stage. The high price could be a concern that prevents homebuyers from purchasing green buildings. However, there is a lack of empirical evidence on whether the premium pricing could be compensated for by the resale price. To address this gap, this study establishes a hedonic regression model to estimate the price premium of green housing at the resale stage. The results show that green housing certified with the Chinese Green Building Label (CGBL) offers a 6% price premium compared with non-green housing at the resale stage. The results also show that green housing with a higher level of green certification, e.g., the 3-star CGBL, provides a greater price premium at resale. The findings indicate that home-buyers can obtain financial compensation for the high cost when purchasing a green home. Our findings also indicate that the price premium for reselling a green home is not always enough to compensate for the purchase cost in different cities. Policy recommendations for government promotion of green housing are also discussed.

Background Pancreatic cancer, of which pancreatic ductal adenocarcinoma (PDAC) is one of the most prevalent type, is one of the most malignant tumors, with a 5-year survival rate of about 10%. Pancreatic cancer stem cells play pivotal roles in chemoresistance and recurrence. Long non-coding RNAs (lncRNAs) have been identified as key regulators of the biological progression of various cancers. LncRNAs were found to be associated with cancer stem cells, which are related to chemoresistance. LINC01137 has been reported as an oncogene in oral squamous cell carcinoma, and bioinformatic analysis found it associated with pancreatic cancer stem cells. This study is aim to discover the function and the underlying mechanism of LINC01137 in pancreatic cancer. Results LINC01137 was pancreatic cancer stem cell-associated lincRNA and associated with stem genes. LINC01137 was upregulated in pancreatic cancer tissues and cell lines. Its high expression correlated with poor prognosis. Knockdown of LINC01137 expression reduced pancreatic cancer stemness, chemoresistance, and proliferation. Mechanistically, LINC01137 mostly located in cytoplasm and exerted its biological function by binding to miR-7155-5p to activate the KLF12/PI3K/AKT pathway. KLF12 also promoted LINC01137 expression. LINC01137 and KLF12 were involved in promoting PDAC tumorigenesis. Conclusion Our results suggested that LINC01137 functions as an oncogene in pancreatic cancer and identified its post-transcriptional regulatory mechanisms, which may contribute to targeted therapy for pancreatic cancer.

We are concerned with the nonlinear Schrodinger-Poisson equation $$\begin{cases}-\Delta u+(V(x)-\lambda)u+\phi(x)u=f(u),\\-\Delta\phi=u^{2},\lim\limits_{\vert x\vert\rightarrow+\infty}\phi(x)=0,x\in \mathbb{R}^{3},\end{cases}\ {\mathrm{(P)}}$$ where λ is a parameter, V (x) is an unbounded potential and f (u) is a general nonlinearity. We prove the existence of a ground state solution and multiple solutions to problem (P).

In this study, we investigated the role of tumor-associated macrophages (TAMs) in the progression of pancreatic ductal adenocarcinoma (PDAC). PDAC patients with higher levels of CD68+ TAMs exhibited shorter overall survival. In Transwell assays, PDAC cells incubated with TAMs or conditioned media from TAM cells (TAM-CM) showed higher migration and invasion rates than controls. PET/CT scan analysis of orthotopic PDAC model mice revealed greater primary tumor growth and liver metastasis in the TAM-CM treatment group than the controls. H&E staining of liver tissues showed significantly higher numbers of metastatic nodules in the TAM-CM treatment group. Heat inactivation of TAM-CM significantly reduced Transwell migration by PDAC cells, suggesting the involvement of one or more secreted proteins in PDAC progression. Transcriptome sequencing analysis of PDAC cells treated with TAM-CM revealed significant enrichment of transforming growth factor-β (TGF-β) signaling pathway genes. Western blot and qRT-PCR analysis showed that TAM-CM enhanced PDAC migration cells by inducing epithelial-to-mesenchymal transition through the TGF-β-Smad2/3/4-Snail signaling axis. The pro-tumorigenic effects of TAMs or TAM-CM were abolished by TGF-β signaling pathway inhibitors and neutralizing TGF-β antibody. These results demonstrate that TAMs promote PDAC progression through the TGF-β signaling pathway.

Heme, as an essential component of hemoproteins, is a prosthetic co-factor found in many cells, which is essential for physiologically vital oxygen transport. However, extracellular or circulatory heme is cytotoxic and triggers inflammation. Although the proinflammatory role of heme has been reported to be associated with Toll-like receptor 4 (TLR4) signaling, the exact mechanism remains unknown. Here, we show that heme promotes TLR4 signaling and inflammation via directly physically interacting with TLR4 and its adaptor protein myeloid differentiation protein 2 (MD2). Genetic loss of MD2 ameliorates heme-induced inflammation and inflammatory cytokine production in the spleen of MD2 knockout (MD2

Background Checkpoint-based immunotherapy has failed to elicit responses in the majority of patients with pancreatic cancer. In our study, we aimed to identify the role of a novel immune checkpoint molecule V-set Ig domain-containing 4 (VSIG4) in pancreatic ductal adenocarcinoma (PDAC). Methods Online datasets and tissue microarray (TMA) were utilized to analyze the expression level of VSIG4 and its correlation with clinical parameters in PDAC. CCK8, transwell assay and wound healing assay were applied to explore the function of VSIG4 in vitro. Subcutaneous, orthotopic xenograft and liver metastasis model were established to explore the function of VSIG4 in vivo. TMA analysis and chemotaxis assay were conducted to uncover the effect of VSIG4 on immune infiltration. Histone acetyltransferase (HAT) inhibitors and si-RNA were applied to investigate factors that regulate the expression of VSIG4. Results Both mRNA and protein levels of VSIG4 were higher in PDAC than normal pancreas in TCGA, GEO, HPA datasets and our TMA. VSIG4 showed positive correlations with tumor size, T classification and liver metastasis. Patients with higher VSIG4 expression were related to poorer prognosis. VSIG4 knockdown impaired the proliferation, migration ability of pancreatic cancer cells both in vitro and in vivo. Bioinformatics study showed positive correlation between VSIG4 and infiltration of neutrophil and tumor-associated macrophages (TAMs) in PDAC and it inhibited the secretion of cytokines. According to our TMA panel, High expression of VSIG4 was correlated with fewer infiltration of CD8+ T cells. Chemotaxis assay also showed knockdown of VSIG4 increased the recruitment of total T cells and CD8+ T cells. HAT inhibitors and knockdown of STAT1 leaded to decreased expression of VSIG4. Conclusions Our data indicates that VSIG4 contribute to cell proliferation, migration and resistance to immune attack, thus identified as a promising target for PDAC treatment with good prognostic value.

Pancreatic cancer, which most commonly refers to pancreatic ductal adenocarcinoma (PDAC), is one of the most malignant tumors, with a 5-year survival rate of about 4%. Pancreatic cancer stem cells play pivotal roles in chemoresistance and recurrence. Long non-coding RNAs (lncRNAs) have been identified as key regulators of the biological progression of various cancers. Recently, lncRNAs were found to be associated with cancer stem cells, which are related to chemoresistance. LINC01137 has been reported as an oncogene in oral squamous cell carcinoma. However, its function and underlying mechanisms in pancreatic cancer remain unclear. Online datasets were used to screen for cancer stem cell-associated lncRNAs and to confirm the relationship between LINC01137 and stem genes. Quantitative real-time PCR was performed to detect RNA expression. In situ hybridization and nucleocytoplasmic separation were used to determine subcellular location. Direct binding of LINC01137 to miR-7155-5p was verified using a dual-luciferase reporter assay. LINC01137 was upregulated in pancreatic cancer tissues and cell lines. Its high expression correlated with advanced pathological stages and poor prognosis. Induction of LINC01137 expression boosted pancreatic cancer stemness, chemoresistance, and proliferation. Mechanistically, LINC01137 exerted its biological function by binding to miR-7155-5p to activate the KLF12/PI3K/AKT pathway. KLF12 also promoted LINC01137 expression. LINC01137 and KLF12 were involved in promoting PDAC tumorigenesis. Our results suggested that LINC01137 functions as an oncogene in pancreatic cancer and identified its post-transcriptional regulatory mechanisms, which may contribute to targeted therapy for pancreatic cancer.

Lung cancer is one of the common types of malignant disorders and the most prevalent cause of cancer-related mortality in the world. Although a wide range of approaches has been examined, strategies in prevention and treatment of lung cancer are still inadequate. Studies show that Vitamin D (VitD) is involved in various biological pathways and has been associated with the etiopathogenesis of several diseases, like cancers. In Vitro and In Vivo experiments have disclosed that VitD plays immunomodulatory and anti-tumor functions. Several lines of evidence have indicated that VitD is involved in the inflammatory settings of the lung. Epidemiological studies have reported that sufficient levels of VitD might be critical in the prevention of lung cancer. Polymorphisms in the genes encoding the different molecules involved in the signaling of VitD might affect the lung cancer risk as well as the quality and quantity of responses to different treatments. In this review article, we intended to clarify the implications of VitD in the normal biology and physiology of the lung and discuss diverse line of evidence about the possible role of VitD in the prevention or treatment of lung cancer.

Let [Formula: see text] be a simple strongly connected digraph and let Aut[Formula: see text] be an automorphism of [Formula: see text]. For [Formula: see text], the set [Formula: see text] is called an orbit of Aut[Formula: see text]. In this paper, first, we show that if [Formula: see text] is a 2-regular strongly connected digraph with two orbits then [Formula: see text], if [Formula: see text] is a [Formula: see text]-regular strongly connected digraph with two orbits and [Formula: see text] [Formula: see text], then [Formula: see text]. Second, we prove that if [Formula: see text], then [Formula: see text]. Last, we characterize the arc atoms of 3-regular strongly connected digraphs with two orbits and [Formula: see text].

Recently numerous studies have demonstrated that neuroinflammation plays a critical role in the pathogenesis of depression. Repetitive transcranial magnetic stimulation (rTMS) has been used to treat depression for years but its mechanism is not fully elucidated. The present study was designed to investigate whether rTMS could alleviate neuroglia-associated neuro-inflammatory process in mice models of depression.Mice were treated with chronic unpredictable mild stress (CUMS) to induce depression models and received four weeks of 15 Hz rTMS. Then the depression-like behaviors, microglia activation, the level of astrocytes, pro-inflammatory cytokines and inflammation-related signaling pathways were evaluated.rTMS ameliorated depression-like behaviors in CUMS-treated mice. rTMS not only markedly alleviated the activation of microglia but induced a switch of microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype in the hippocampus and prefrontal cortex. Meanwhile, rTMS reversed the down-regulation of astrocytes and inhibited high levels of interleukin (IL)-6, IL-1β and tumor necrosis factor-alpha (TNF-α) caused by CUMS in above regions. Moreover, we found that anti-inflammatory actions by rTMS were associated with the TLR4/NF-κB/NLRP3 signaling pathway.Collectively, our findings indicate that rTMS can exert anti-inflammatory actions in depression and provide new insights into the mechanism of rTMS in the treatment of depression.

OX40 signaling pathway occupies a vital place in anti-tumor immunity; however, the role of tumor-infiltrating OX40A total of 325 sequential PDAC patients who received curative tumor resection between January 2014 and December 2016 were enrolled. Tissues of these patients were immunohistochemically assessed for tumor infiltration of CD4Our results showed that higher OX40This study demonstrated that intratumoral infiltration by a high number of OX40

Background Variants in the endosomal solute carrier family 9 member A6 (SLC9A6)/(Na+,K+)/H+ exchanger 6 (NHE6) gene have been linked to epilepsy, speech loss, truncal ataxia, hyperkinesia, and postnatal microcephaly. Methods In the present study, we evaluated genetic alterations in a 3‐year‐old Chinese boy displayed features of epilepsy, psychomotor retardation, microcephaly, low body weight, difficulty in feeding, excessive movement, attention loss, ataxia, and cerebellar atrophy and his healthy family using WES method. The identified variant was further confirmed by Sanger sequencing method. Finally, minigene assays were used to verify whether the novel SLC9A6 intronic variant influenced the normal splicing of mRNA. Results We identified a novel hemizygous splicing variant [NM_001042537.1: c.1463‐1G>A] in SLC9A6 by trio‐based exome sequencing. The minigene expression in vitro confirmed the splicing variant altered a consensus splice acceptor site of SLC9A6 intron 11, resulting in skipping over exon 12. Conclusions Our finding extends the catalog of pathogenic intronic variants affecting SLC9A6 pre‐mRNA splicing and provides a basis for the genetic diagnosis of CS., We report on a case of 3‐year‐old Chinese boy with Christianson Syndrome (CS) displayed the features of epilepsy, psychomotor retardation, microcephaly, low body weight, difficulty in feeding, excessive movement, attention loss, ataxia, and cerebellar atrophy. We identified a novel homozygous splicing variant [c.1463–1 (IVS11) G >A] in SLC9A6 by trio‐based exome sequencing. The minigene expression in vitro confirmed the splicing variant altered a consensus splice acceptor site of SLC9A6 intron 11, resulting in skipping over exon 12. Our finding extends the catalog of pathogenic intronic mutations affecting SLC9A6 pre‐mRNA splicing and provides a basis for the genetic diagnosis of CS.

Microtubules (MTs) are highly dynamic polymers essential for a wide range of cellular physiologies, such as acting as directional railways for intracellular transport and position, guiding chromosome segregation during cell division, and controlling cell polarity and morphogenesis. Evidence has established that maintaining microtubule (MT) stability in neurons is vital for fundamental cellular and developmental processes, such as neurodevelopment, degeneration, and regeneration. To fulfill these diverse functions, the nervous system employs an arsenal of microtubule-associated proteins (MAPs) to control MT organization and function. Subsequent studies have identified that the disruption of MT function in neurons is one of the most prevalent and important pathological features of traumatic nerve damage and neurodegenerative diseases and that this disruption manifests as a reduction in MT polymerization and concomitant deregulation of the MT cytoskeleton, as well as downregulation of microtubule-associated protein (MAP) expression. A variety of MT-targeting agents that reverse this pathological condition, which is regarded as a therapeutic opportunity to intervene the onset and development of these nervous system abnormalities, is currently under development. Here, we provide an overview of the MT-intrinsic organization process and how MAPs interact with the MT cytoskeleton to promote MT polymerization, stabilization, and bundling. We also highlight recent advances in MT-targeting therapeutic agents applied to various neurological disorders. Together, these findings increase our current understanding of the function and regulation of MT organization in nerve growth and regeneration.

This study was designed to explore the relative efficacy and toxicity of upfront radiotherapy (RT) and late RT in combination treatments for patients with limited-stage extranodal natural killer/T-cell lymphoma nasal type (LS-ENKTL). We searched for clinical trials in the PubMed database that compared upfront RT with late RT in the combined treatment of patients with LS-ENKTL. We systematically evaluated the differences in survival, treatment response, and treatment-related adverse events (AEs) between these two groups. Ten retrospective studies with a total of 1752 patients were included. Upfront RT significantly prolonged the overall survival (OS) and progression-free survival (PFS) of patients compared to late RT in combination with chemotherapy (CT) (HR = 0.72, 95% CI 0.59-0.88, P = 0.001 for OS; HR = 0.57, 95% CI 0.41-0.79, P = 0.0007 for PFS). The complete remission (CR) rate in the upfront RT group was superior to that in the late RT group (HR = 1.61, 95% CI 1.09-2.37, P = 0.02). Patients experienced similar local recurrence-free survival (LRFS), objective response rates (ORR), and toxicity between these two arms (P > 0.05 for all) in the analysis of each subgroup. The survival benefit of upfront RT was not correlated with the RT dose, concurrent chemoradiotherapy (CCRT) (or not), or the CT regimen (P > 0.05 for all). Without compromises in terms of toxicity, RT dose, and treatment modality, upfront RT can significantly benefit OS, PFS, and CR compared to late RT in combination treatment. These findings verified that the upfront RT regimen is more suitable for patients with LS-ENKTL.

Background: Acute liver injury (ALI) involves excessive oxidative stress(OS) and inflammatory responses, leading to a high mortality rate due to lack of effective therapy. Carbon tetrachloride (CCl4) is widely used to induce ALI by induction of reactive oxygen species. Probiotics, including Lactobacillus plantarum ST-III, have been shown to produce antibacterial and antioxidant substances such as organic acids or bacteriocins that reduce liver damage. Nevertheless, the effect of Lactobacillus plantarum ST-III culture supernatant (L-P-cs) on CCl4-induced liver injury remains unclear.Methods: Mice were pretreated with L-P-cs or medium for 14days before one dose of 0.2% CCl4 at 10ml/kg body weight delivered by intraperitoneal injection. CCl4-induced liver injury was examined by measuring serum levels of liver transaminases and high mobility-group box 1 protein (HMGB1) and liver histological staining. Inflammation and apoptosis in liver were evaluated by real-time PCR, enzyme-linked immunosorbent assay (ELISA), and TUNEL staining. Apoptosis in NCTC 1469 cells was detected using CCK8 and western blotting (WB). In liver, OS and endoplasmic reticulum stress(ERS)-related proteins were measured using kits and WB.Results: L-P-cs significantly ameliorated CCl4-induced liver injury and reduced CCl4- induced inflammatory response and apoptosis, consistent with NCTC 1469 cells' results. L-P-cs also restored CCl4-induced increases in cell OS and ERS to normalize liver function. Specifically, L-P-cs pretreatment decreased CCl4-induced increases in nuclear factor (erythroid-2 related) factor 2, HO-1, superoxide dismutase, glucose regulatory protein, and activating transcription factor 6.Conclusion: L-P-cs synergistically improves liver lobule necrosis, hepatocyte inflammation, and apoptosis by reducing liver OS and ERS.

In this paper, we give a variational analysis to the planar dual Minkowski problem in the Sobolev space. With the new variational characterization, we can deal with existence results for prescribed not necessarily positive data. Meanwhile, functional inequalities and multiple solutions are also obtained.