Inorganic Halide Perovskite Nanowires/Conjugated Polymer Heterojunction-Based Optoelectronic Synaptic Transistors for Dynamic Machine Vision.

Inspired by the retina, artificial optoelectronic synapses have groundbreaking potential for machine vision. The field-effect transistor is a crucial platform for optoelectronic synapses that is highly sensitive to external stimuli and can modulate conductivity. On the basis of the decent optical absorption, perovskite materials have been widely employed for constructing optoelectronic synaptic transistors. However, the reported optoelectronic synaptic transistors focus on the static processing of independent stimuli at different moments, while the natural visual information consists of temporal signals. Here, we report CsPbBrI2 nanowire-based optoelectronic synaptic transistors to study the dynamic responses of artificial synaptic transistors to time-varying visual information for the first time. Moreover, on the basis of the dynamic synaptic behavior, a hardware system with an accuracy of 85% is built to the trajectory of moving objects. This work offers a new way to develop artificial optoelectronic synapses for the construction of dynamic machine vision systems.

Controllable Fluorocarbon Chain Elongation: TMSCF2Br-Enabled Trifluorovinylation and Pentafluorocyclopropylation of Aldehydes.

Controllable fluorocarbon chain elongation (CFCE) is a promising yet underdeveloped strategy for the well-defined synthesis of structurally novel polyfluorinated compounds. Herein, the direct and efficient trifluorovinylation and pentafluorocyclopropylation of aldehydes are described by using TMSCF2Br (TMS = trimethylsilyl) as the sole fluorocarbon source, accomplishing the goals of CFCE from C1 to C2 and from C1 to C3, respectively. The key to the success of these CFCE processes lies in the unique and diversified chemical reactivity of TMSCF2Br, which can serve as two different precursors, namely, a TMSCF2 radical precursor and a difluorocarbene precursor. Various functional groups are amenable to this new synthetic protocol, providing streamlined access to a broad range of alcohols containing trifluorovinyl or pentafluorocyclopropyl moieties from abundantly available aldehydes. The potential utility of these methods is further demonstrated by the gram-scale synthesis, derivatization, and measurement of log P values of the products.

Ochratoxin A-enhanced glycolysis induces inflammatory responses in human gastric epithelium cells through mTOR/HIF-1α signaling pathway.

Ochratoxin A (OTA) is a mycotoxin commonly found in several food commodities worldwide with potential nephrotoxic, hepatotoxic and carcinogenic effects. We previously showed for the first time that OTA treatment enhanced glycolysis in human gastric epithelium (GES-1) cells in vitro. Here, we found that OTA exposure activated inflammatory responses, evidenced by increasing of NF-κB signaling pathway-related protein (p-p65 and p-IκBα) expressions and elevating of inflammatory cytokine (IL-1ß and IL-6) mRNA expressions in GES-1 cells. To elucidate the role of glycolysis in inflammatory effects triggered by OTA, we pretreated GES-1 cells with glycolysis inhibitor (2-deoxy-D-glucose, 2-DG) before OTA exposure. The result showed that 2-DG reduced the protein expressions of p-p65 and p-IκBα and alleviated the mRNA expressions of inflammatory cytokines in OTA-treated GES-1 cells. Furthermore, OTA activated the mTOR/HIF-1α pathway by increasing the protein expressions of p-mTOR, p-eIF4E and HIF-1α, and inhibition of mTOR with rapamycin or silencing HIF-1α with siRNA significantly attenuated OTA-enhanced glycolysis by reducing glycolysis related genes and thereby decreasing inflammatory effects of GES-1 cells. These results demonstrate that OTA activates inflammatory responses in GES-1 cells and this is controlled by mTOR/HIF-1α pathway-mediated glycolysis enhancement. Our findings provide a novel mechanistic view into OTA-induced gastric cytotoxicity.

Germacrone alleviates breast cancer-associated osteolysis by inhibiting osteoclastogenesis via inhibition of MAPK/NF-κB signaling pathways.

Bone is one of the most frequent sites for metastasis in breast cancer patients. Bone metastasis significantly reduces the survival time and the life quality of breast cancer patients. Germacrone (GM) can serve humans as an anti-cancer and anti-inflammation agent, but its effect on breast cancer-induced osteolysis remains unclear. This study aims to investigate the functions and mechanisms of GM in alleviating breast cancer-induced osteolysis. The effects of GM on osteoclast differentiation, bone resorption, F-actin ring formation, and gene expression were examined in vitro. RNA-sequencing and Western Blot were conducted to explore the regulatory mechanisms of GM on osteoclastogenesis. The effects of GM on breast cancer-induced osteoclastogenesis, and breast cancer cell malignant behaviors were also evaluated. The in vivo efficacy of GM in the ovariectomy model and breast cancer bone metastasis model with micro-CT and histomorphometry. GM inhibited osteoclastogenesis, bone resorption and F-actin ring formation in vitro. Meanwhile, GM inhibited the expression of osteoclast-related genes. RNA-seq analysis and Western Blot confirmed that GM inhibited osteoclastogenesis via inhibition of MAPK/NF-κB signaling pathways. The in vivo mouse osteoporosis model further confirmed that GM inhibited osteolysis. In addition, GM suppressed the capability of proliferation, migration, and invasion and promoted the apoptosis of MDA-MB-231 cells. Furthermore, GM could inhibit MDA-MB-231 cell-induced osteoclastogenesis in vitro and alleviate breast cancer-associated osteolysis in vivo human MDA-MB-231 breast cancer bone metastasis-bearing mouse models. Our findings identify that GM can be a promising therapeutic agent for patients with breast cancer osteolytic bone metastasis.

Unveiling fenpropathrin resistance levels in field populations of Tetranychus cinnabarinus (Boisduval): Insights, risks, and RNAi strategy.

Indoor cases of Tetranychus cinnabarinus displaying resistance have been documented, but the resistance level in field populations remains unexplored in China. This study delves into the resistance dynamics of T. cinnabarinus to fenpropathrin in various field populations across China, a pressing concern in contemporary agricultural pest control. The conventional bioassay and amplicon sequencing reveal a notable absence of significant fenpropathrin resistance in field populations, contrasting with known resistance in indoor cases. Current study highlights the limitations of traditional bioassays in detecting early-stage resistance and underscores the nuanced capabilities and constraints of amplicon sequencing in resistance gene frequency analysis. By employing an integrated approach, we combined dose-response bioassays, amplicon sequencing, and statistical modeling to assess resistance levels and investigate underlying genetic factors. The model with empirical data indicates that a 5% mutation frequency represents the threshold before resistance emerges. However, the detection of the kdr mutation in certain populations ranging from 0 to 1.2%, signals an early looming threat of future resistance emergence. Additionally, we further assessed a specific dsRNA targeting VGSC genes at two concentrations (10 ng/µL and 100 ng/µL), both inducing substantial mortality by silencing target genes effectively. The exploration of RNA interference (RNAi) as a novel, more environmentally friendly pest control measure opens new avenues, despite the ongoing challenge of resistance evolution. Overall, this study underscores the necessity for evolving pest management strategies, integrating advanced biotechnological approaches with traditional methods, to effectively counter pesticide resistance and ensure sustainable agricultural productivity.

Tumor Necrosis Factor α-Dependent Lung Inflammation Promotes the Progression of Lung Adenocarcinoma Originating From Alveolar Type II Cells by Upregulating MIF-CD74.

Lung adenocarcinoma is the most common type of lung cancer. We recently reported that inflammation-driven lung adenocarcinoma (IDLA) originates from alveolar type (AT)-II cells, which depend on major histocompatibility complex (MHC) class II to promote the expansion of regulatory T cells. The MHC class II-associated invariant chain (CD74) binds to the macrophage migration inhibitory factor (MIF), which is associated with promoting tumor growth and invasion. However, the role of MIF-CD74 in the progression of lung adenocarcinoma and the underlying mechanisms remain unclear. We aimed to explore the role of MIF-CD74 in the progression of lung adenocarcinoma and elucidate the mechanisms by which tumor necrosis (TNF)-α-mediated inflammation regulates CD74 and MIF expression in IDLA. In human lung adenocarcinoma, CD74 was upregulated on the surface of tumor cells originating from AT-II cells, which correlated positively with lymph node metastasis, tumor origin/nodal involvement/metastasis stage, and TNF-α expression. MIF interaction with CD74 promoted the proliferation and migration of A549 and H1299 cells in vitro. Using a urethane-induced IDLA mouse model, we observed that CD74 was upregulated in tumor cells and macrophages. MIF expression was upregulated in macrophages in IDLA. Blocking TNF-α-dependent inflammation downregulated CD74 expression in tumor cells and CD74 and MIF expression in macrophages in IDLA. Conditioned medium from A549 cells or activated mouse AT-II cells upregulated MIF in macrophages by secreting TNF-α. TNF-α-dependent lung inflammation contributes to the progression of lung adenocarcinoma by upregulating CD74 and MIF expression, and AT-II cells upregulate MIF expression in macrophages by secreting TNF-α. This study provides novel insights into the function of CD74 in the progression of IDLA.

Novel Semiconductive Ternary Hybrid Heterostructures for Artificial Optoelectronic Synapses.

Synaptic devices that mimic biological synapses are considered as promising candidates for brain-inspired devices, offering the functionalities in neuromorphic computing. However, modulation of emerging optoelectronic synaptic devices has rarely been reported. Herein, a semiconductive ternary hybrid heterostructure is prepared with a D-D'-A configuration by introducing polyoxometalate (POM) as an additional electroactive donor (D') into a metalloviologen-based D-A framework. The obtained material features an unprecedented porous 8-connected bcu-net that accommodates nanoscale [α-SiW12 O40 ]4- counterions, displaying uncommon optoelectronic responses. Besides, the fabricated synaptic device based on this material can achieve dual-modulation of synaptic plasticity due to the synergetic effect of electron reservoir POM and photoinduced electron transfer. And it can successfully simulate learning and memory processes similar to those in biological systems. The result provides a facile and effective strategy to customize multi-modality artificial synapses in the field of crystal engineering, which opens a new direction for developing high-performance neuromorphic devices.

TNF-α-dependent lung inflammation upregulates PD-L1 in monocyte-derived macrophages to contribute to lung tumorigenesis.

Chronic inflammation, which is dominated by macrophage-involved inflammatory responses, is an instigator of cancer initiation. Macrophages are the most abundant immune cells in healthy lungs, and associated with lung tumor development and promotion. PD-L1 is a negative molecule in macrophages and correlated with an immunosuppressive function in tumor environment. Macrophages expressing PD-L1, rather than tumor cells, exhibits a critical role in tumor growth and progression. However, whether and how PD-L1 in macrophages contributes to inflammation-induced lung tumorigenesis requires further elucidation. Here, we found that higher expression of PD-L1 in CD11b+ CD206+ macrophages was positively correlated with tumor progression and PD-1+ CD8+ T cells population in human adenocarcinoma patients. In the urethane-induced inflammation-driven lung adenocarcinoma (IDLA) mouse model, the infiltration of circulating CD11bhigh F4/80+ monocyte-derived macrophages (MoMs) was increased in pro-tumor inflamed lung tissues and lung adenocarcinoma. PD-L1 was mainly upregulated in MoMs associated with enhanced T cells exhaustion in lung tissues. Anti-PD-L1 treatment can reduce T cells exhaustion at pro-tumor inflammatory stage, and then inhibit tumorigenesis in IDLA. The pro-tumor lung inflammation depended on TNF-α to upregulate PD-L1 and CSN6 expression in MoMs, and induced cytokines production by alveolar type-II cells (AT-II). Furthermore, inflammatory AT-II cells could secret TNF-α to upregulate PD-L1 expression in bone-marrow driven macrophages (BM-M0). Inhibition of CSN6 decreased PD-L1 expression in TNF-α-activated macrophage in vitro, suggesting a critical role of CSN6 in PD-L1 upregulation. Thus, pro-tumor inflammation can depend on TNF-α to upregulate PD-L1 in recruited MoMs, which may be essential for lung tumorigenesis.

Artificial Tactile Sensing System with Photoelectric Output for High Accuracy Haptic Texture Recognition and Parallel Information Processing.

Developing multifunctional artificial sensory systems is an important task for constructing future artificial neural networks. A system with multisignal output capability is highly required by the rising demand for high-throughput data processing in the Internet of Things (IoT) society. Here, a novel dual-output artificial tactile sensing (DOATS) system with parallel output of photoelectric signals was proposed. Because of the ionic-electronic coupling mechanism in light-emitting synaptic (LES) devices in the DOATS system, modulating electric current and light emission can coexist through ion accumulation and electron-hole recombination. As a result, the DOATS system can realize the simulation of human tactile information, and the recognition of 16 kinds of fabrics was demonstrated with an accuracy rate of 94.1%. A photoelectric hybrid artificial neural network was proposed, which achieved efficient and accurate multitask operation. The DOATS system proposed in this work is promising for implementing photoelectric hybrid neural network and promoting the development of interactive artificial intelligence.

Risk factors of postoperative neurodevelopmental abnormalities in neonates with critical congenital heart disease. / å±é‡å ˆå¤©æ€§å¿ƒè„ç— æ–°ç”Ÿå„¿æœ¯åŽæ–°å‘ç¥žç»å‘è‚²å¼‚å¸¸çš„å±é™©å› ç´ .

OBJECTIVES: To investigate the risk factors of postoperative neuro-developmental abnormalities in neonates with critical congenital heart disease (CCHD). METHODS: Clinical data of 50 neonates with CCHD admitted in the Cardiac Intensive Care Unit, The Children's Hospital, Zhejiang University School of Medicine from November 2020 to December 2021 were retrospectively analyzed. Neurological assessment was performed with cranial ultrasonography, CT/MRI, video electroencephalogram and clinical symptoms before and after surgical treatment for all patients, and neurodevelopmental abnormalities were documented. Binary logistic stepwise regression was used to analyze risk factors of postoperative new-onset neurodysplasia in children with CCHD, and the predictive value of the risk factors on postoperative neurodevelopmental abnormalities were evaluated using the receiver operating characteristic (ROC) curve. RESULTS: Neurodevelopmental abnormalities were detected in 22 cases (44.0%) and not detected in 28 cases (56.0%) before surgery. There were no significant differences in gender, birth weight, age at admission, gestational age, preoperative SpO2 level, prematurity, cyanotic congenital heart disease, and ventilator support between the two groups (all P>0.05). After surgery, there were 22 cases (44.0%) with new-onset neurological abnormalities and 28 cases (56.0%) without new-onset abnormalities. Multivariate logistic regression analysis showed that postoperative 24 h peak lactic acid (OR=1.537, 95%CI: 1.170-2.018, P<0.01) and postoperative length of ICU stay (OR=1.172, 95%CI:1.031-1.333, P<0.05) were independent risk factors for postoperative new-onset neurodevelopmental abnormalities. The area under ROC curve (AUC) of the postoperative 24 h peak lactic acid for predicting the new-onset neurological abnormalities after operation was 0.829, with cut-off value of 4.95 mmol/L. The diagnostic sensitivity and specificity were 90.0% and 64.3%, respectively. The AUC of postoperative length of ICU stay for predicting the new-onset neurological abnormalities after operation was 0.712, with cut-off value of 18.0 d. The diagnostic sensitivity and specificity were 50.0% and 96.4%, respectively. The AUC of the combination of the two indicators was 0.917, the diagnostic sensitivity and specificity were 95.5% and 64.3%, respectively. CONCLUSIONS: The incidence of neurodysplasia in neonatal CCHD is high, and new neurological abnormalities may occur after surgery. The postoperative 24 h peak lactic acid and postoperative length of ICU stay are risk factors for new-onset neurodysplasia after surgery. The combination of the two indicators has good predictive value for neurodevelopmental outcomes after surgery in CCHD infants.

Treatment of symptomatic hip dysplasia by posterolateral small incision assisted Bernese periacetabular osteotomy.

BACKGROUND: For periacetabular osteotomy, traditional approaches usually have a long learning curve. We aimed to evaluate the postoperative results and complications of periacetabular osteotomy under a new double-incision approach. METHODS: The records of 58 consecutive patients (65 hips) who underwent periacetabular osteotomy using the new approach were retrospectively reviewed and evaluated. There were 52 women and 6 men with a mean age of 28.1 years at the time of surgery. RESULTS: The average follow-up period was 35.2 months, during which no patients were converted to total hip arthroplasty. Complications included 6 hips (9.2%) with nerve dysesthesias and 1 hip (1.5%) with delayed wound healing. The mean operative time and intraoperative blood loss were 88.6 min and 402.8 ml, respectively. The mean modified Harris hip score had improved from 72.2 points preoperatively to 91.3 points at the last follow-up. Fifty-five patients (62 hips, 95.4%) were satisfied to their outcomes, and good preoperative functional score was associated with a satisfactory outcome. Furthermore, the average lateral center-edge angle, anterior center-edge angle and acetabular index angle were corrected well after surgery. CONCLUSION: Periacetabular osteotomy using modified Smith-Petersen or Bikini approach with posterolateral assisted small incision can be performed safely and with satisfactory results. In addition, this technique shortens the learning curve, and reduces the operating complexity, especially for beginner.

Lung adenocarcinoma-related TNF-α-dependent inflammation upregulates MHC-II on alveolar type II cells through CXCR-2 to contribute to Treg expansion.

MHC-II on alveolar type-II (AT-II) cells is associated with immune tolerance in an inflammatory microenvironment. Recently, we found TNF-α upregulated MHC-II in AT-II in vitro. In this study, we explored whether TNF-α-mediated inflammation upregulates MHC-II on AT-II cells to trigger Treg expansion in inflammation-driven lung adenocarcinoma (IDLA). Using urethane-induced mice IDLA model, we found that IDLA cells mainly arise from AT-II cells, which are the major source of MHC-II. Blocking urethane-induced inflammation by TNF-α neutralization inhibited tumorigenesis and reversed MHC-II upregulation on tumor cells of AT-II cellular origin in IDLA. MHC-II-dependent AT-II cells were isolated from IDLA-induced Treg expansion. In human LA samples, we found high expression of MHC-II in tumor cells of AT-II cellular origin, which was correlated with increased Foxp3+ T cells infiltration as well as CXCR-2 expression. CXCR-2 and MHC-II colocalization was observed in inflamed lung tissue and IDLA cells of AT-II cellular origin. Furthermore, at the pro-IDLA inflammatory stage, TNF-α-neutralization or CXCR-2 deficiency inhibited the upregulation of MHC-II on AT-II cells in inflamed lung tissue. Thus, tumor cells of AT-II cellular origin contribute to Treg expansion in an MHC-II-dependent manner in TNF-α-mediated IDLA. At the pro-tumor inflammatory stage, TNF-α-dependent lung inflammation plays an important role in MHC-II upregulation on AT-II cells.

Modeling the outbreak and control of African swine fever virus in large-scale pig farms.

African swine fever virus (ASFV) leads to a highly contagious, lethal and economically devastating disease among pigs. Since no effective treatment for the disease, it is crucial to investigate its transmission mechanism and control strategies in large-scale pig farms. We first established a toy model to explore ASFV spread in one pig unit. Then a switching patch model was developed to capture its spread from one initial epidemic pig house consecutively to others, even the whole farm. Assessing innocent culling rates of three large-scale epidemic pig farms in Jiangsu Province showed that it is unnecessary to slaughter all pigs in the farms compulsively. Then we explored how the disinfection and fixation of employees impact ASFV spread in the farms. To control ASFV, we can block or slow down its spreading by improving the efficiency of disinfection and decreasing employee population to some extend. We can also shrink potential areas to be infected by properly improving the matching refinement degree among employees and houses. Some essential requirements for large-scale pig farms are presented to reduce their ASFV spreading risk, which can be helpful for animal health authorities in establishing regulation to standardize large-scale pig farms.

Functions and mechanisms of circular RNAs in regulating stem cell differentiation.

Stem cells are a class of undifferentiated cells with great self-renewal and differentiation capabilities that can differentiate into mature cells in specific tissue types. Stem cell differentiation plays critical roles in body homoeostasis, injury repair and tissue generation. The important functions of stem cell differentiation have resulted in numerous studies focusing on the complex molecular mechanisms and various signalling pathways controlling stem cell differentiation. Circular RNAs (circRNAs) are a novel class of noncoding RNAs with a covalently closed structure present in eukaryotes. Numerous studies have highlighted important biological functions of circRNAs, and they play multiple regulatory roles in various physiological and pathological processes. Importantly, multiple lines of evidence have shown the abnormal expression of numerous circRNAs during stem cell differentiation, and some play a role in regulating stem cell differentiation, highlighting the role of circRNAs as novel biomarkers of stem cell differentiation and novel targets for stem cell-based therapy. In this review, we systematically summarize and discuss recent advances in our understanding of the roles and underlying mechanisms of circRNAs in modulating stem cell differentiation, thus providing guidance for future studies to investigate stem cell differentiation and stem cell-based therapy.Abbreviations: CircRNAs: circular RNAs; ESCs: embryonic stem cells; ADSCs: adipose-derived mesenchymal stem cells; ecircRNAs: exonic circRNAs; EIciRNAs: exon-intron circRNAs; eiRNAs: circular intronic RNAs; tricRNAs: tRNA intronic circRNAs; pol II: polymerase II; snRNP: small nuclear ribonucleoprotein; m6A: N6-methyladenosine; AGO2: Argonaute 2; RBPs: RNA-binding proteins; MBNL: muscleblind-like protein 1; MSCs: mesenchymal stem cells; hiPSCs: human induced pluripotent stem cells; hiPSC-CMs: hiPSC-derived cardiomyocytes; hBMSCs: human bone marrow mesenchymal stem cells; hADSCs: human adipose-derived mesenchymal stem cells; hDPSCs: human dental pulp stem cells; RNA-seq: high-throughput RNA sequencing; HSCs: haematopoietic stem cells; NSCs: neural stem cells; EpSCs: epidermal stem cells; hESCs: human embryonic stem cells; mESCs: murine embryonic stem cells; MNs: motor neurons; SSUP: small subunit processome; BMSCs: bone marrow-derived mesenchymal stem cells; OGN: osteoglycin; GIOP: glucocorticoid­induced osteoporosis; CDR1as: cerebellar degeneration-related protein 1 transcript; SONFH: steroid-induced osteogenesis of the femoral head; rBMSCs: rat bone marrow-derived mesenchymal stem cells; QUE: quercetin; AcvR1b: activin A receptor type 1B; BSP: bone sialoprotein; mADSCs: mouse ADSCs; PTBP1: polypyrimidine tract-binding protein; ER: endoplasmic reticulum; hUCMSCs: MSCs derived from human umbilical cord; MSMSCs: maxillary sinus membrane stem cells; SCAPs: stem cells from the apical papilla; MyoD: myogenic differentiation protein 1; MSTN: myostatin; MEF2C: myocyte enhancer factor 2C; BCLAF1: BCL2-associated transcription factor 1; EpSCs: epidermal stem cells; ISCs: intestinal stem cells; NSCs: neural stem cells; Lgr5+ ISCs: crypt base columnar cells; ILCs: innate lymphoid cells.

Nicotinamide adenine dinucleotide promotes synaptic plasticity gene expression through regulation N-methyl-D-aspartate receptor/Ca2+/Erk1/2 pathway.

Nicotinamide adenine dinucleotide (NADH) has been reported to regulate synaptic plasticity recently, while its role in this process remains unclear. To explore the contribution and the underlying mechanisms of NADH regulating synaptic plasticity, here, we examined NADH's effect on immediate-early response genes (IEGs) expressions, including C-Fos and Arc in primary cultured cortical neurons and the frontal cortex of mouse brain. Our results showed that NADH promoted IEGs expression and that the C-Fos and Arc levels are increased in primary cultured cortical neurons, which is almost completely blocked by N-methyl-D-aspartate receptor (NMDAR) inhibitor, MK-801. Moreover, NADH significantly increased intracellular Ca2+ levels and the phosphorylation of Erk1/2, a downstream molecule of the NMDAR. Furthermore, NADH also significantly increased IEGs expression in vivo, accompanied by the changes of Ca2+ in neurons and activation of excitatory neurons in the mouse frontal cortex. In conclusion, this study indicates that NADH can promote the expression of synaptic plasticity-related IEGs through the NMDAR/Ca2+/Erk1/2 pathway, which provides a new way to understand the regulatory role of NADH in synaptic plasticity.

EGFR-ERK pathway regulates CSN6 to contribute to PD-L1 expression in glioblastoma.

Glioblastoma (GBM) is the most common and malignant brain tumor in adults. Recently, programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint blockades have been applied for GBM treatment. However, the mechanism of PD-L1 upregulation in GBM is still unclear. COP9 signalosome 6 (CSN6) is crucial for maintaining the protein stabilization in cancer cells. In this study, we applied human GBM specimens and cell lines to investigate whether the EGFR-ERK pathway regulates CSN6 for PD-L1 upregulation. Data from The Cancer Genome Atlas dataset showed that high expression of EGFR, CSN6, and PD-L1 in patients with glioma was associated with poor prognosis. In 47 human GBM specimens, high expression of PD-L1 was associated with low amount of CD8+ T cell infiltration as well as the poor prognosis of patients. CSN6 was positively correlated with EGFR and PD-L1 expression in human GBM specimens. We treated two GBM cell lines (U87 and U251) with epidermal growth factor (EGF) in vitro, and found EGF-upregulated p-EGFR, p-ERK, CSN6, and PD-L1 expression in GBM cells. PD98059, the ERK blocker, inhibited upregulations of CSN6 and PD-L1 in EGF-treated cells. Inhibition of CSN6 by small interfering RNA decreased PD-L1 expression but also increased CHIP expression in GBM cells. When the cells were treated with EGF and cycloheximide (CHX), a protein synthesis inhibitor, EGF-reduced CHX-induced CSN6 and PD-L1 turnover in GBM cells. Furthermore, CSN6-mediated downregulation of PD-L1 was inhibited by MG132, a proteasome inhibitor in U87 cells. Thus, these results suggest that the EGFR-ERK pathway may upregulate CSN6, which may inhibit PD-L1 degradation and subsequently maintain PD-L1 stability in GBM.

TNF-α-dependent lung inflammation upregulates superoxide dismutase-2 to promote tumor cell proliferation in lung adenocarcinoma.

Manganese superoxide dismutase (SOD-2), an important primary antioxidant enzyme located in mitochondria, plays a critical role in tumor progression. Reportedly, the proinflammatory cytokine, tumor necrosis factor (TNF)-α, can increase SOD-2 expression in a human lung adenocarcinoma cell line in vitro, indicating that TNF-α-mediated inflammation may regulate SOD-2 expression, which may be related to cancer promotion. Using a urethane-induced inflammation-driven lung adenocarcinoma (IDLA) mice model, we investigated whether and how TNF-α-mediated inflammation upregulated SOD-2 expression in lung adenocarcinoma. Our results showed that SOD-2 was mostly expressed on surfactant protein-C+ AT-II cells (alveolar type II cell) and tumor cells in IDLA mice, which were surrounded by CD68+ macrophages. Blocking TNF-α-dependent inflammation downregulated SOD-2 expression in inflamed lung tissues at the protumor stage and also inhibited SOD-2 expression in tumor cells in the IDLA model. In human lung adenocarcinoma, both the number of infiltrating CD68+ macrophages and TNF-α expression correlated positively with SOD-2 expression, which is related to lymph node metastasis and TNM stage. We collected the conditioned medium from lipopolysaccharide-activated phorbol myristate acetate-induced THP1 (M1) cells to stimulate A549 and H1299 cells and observed that THP1-M1 upregulated SOD-2 by secreting TNF-α. Blocking SOD-2 expression significantly inhibited TNF-α-induced cell proliferation in A549 and H1299 cells in vitro. Thus, TNF-α-mediated lung inflammation can upregulate SOD-2 expression in lung adenocarcinoma, and macrophages contribute to SOD-2 upregulation by secreting TNF-α.

Modeling and dynamics of Wolbachia-infected male releases and mating competition on mosquito control.

Despite centuries of continuous efforts, mosquito-borne diseases (MBDs) remain enormous health threat of human life worldwide. Lately, the USA government has approved an innovative technology of releasing Wolbachia-infected male mosquitoes to suppress the wild mosquito population. In this paper we first introduce a stage-structured model for natural mosquitos, then we establish a new model considering the releasing of Wolbachia-infected male mosquitoes and the mating competition between the natural male mosquitoes and infected males on the suppression of natural mosquitoes. Dynamical analysis of the two models, including the existence and local stability of the equilibria and bifurcation analysis, reveals the existence of a forward bifurcation or a backward bifurcation with multiple attractors. Moreover, globally dynamical properties are further explored by using Lyapunov function and theory of monotone operators, respectively. Our findings suggest that infected male augmentation itself cannot always guarantee the success of population eradication, but leads to three possible levels of population suppression, so we define the corresponding suppression rate and estimate the minimum release ratio for population eradication. Furthermore, we study how the release ratio of infected males and natural ones, mating competition, the rate of cytoplasmic incompatibility and the basic offspring number affect the suppression rate of natural mosquitoes. Our results show that the successful eradication relies on assessing the reproductive capacity of natural mosquitoes, a selection of suitable Wolbachia strains and an appropriate release amount of infected males. This study will be helpful for public health authorities in designing proper strategies to control vector mosquitoes and prevent the epidemics of MBDs.

Aflatoxin G1 induced TNF-α-dependent lung inflammation to enhance DNA damage in alveolar epithelial cells.

Aflatoxin G1 (AFG1 ), a member of the AF family with cytotoxic and carcinogenic properties, could cause DNA damage in alveolar type II (AT-II) cells and induce lung adenocarcinoma. Recently, we found AFG1 could induce chronic lung inflammation associated with oxidative stress in the protumor stage. Chronic inflammation plays a critical role in cigarette smoke or benzo[a]pyrene-induced lung tissues damage. However, it is unclear whether and how AFG1 -induced lung inflammation affects DNA damage in AT-II cells. In this study, we found increased DNA damage and cytochrome P450 (CYP2A13) expression in AFG1 -induced inflamed lung tissues. Furthermore, we treated the mice with a soluble tumor necrosis factor (TNF)-α receptor and AFG1 and found that TNF-α neutralization inhibited the AFG1 -induced chronic lung inflammation in vivo, and then reversed the CYP2A13 expression and DNA damage in AT-II cells. The results suggest that AFG1 induces TNF-α-dependent lung inflammation to regulate 2A13 expression and enhance DNA damage in AT-II cells. Then, we treated the primary mice AT-II cells and human AT-II like cells (A549) with AFG1 and TNF-α and found that TNF-α enhanced the AFG1 -induced DNA damage in mice AT-II cells as well as A549 cells in vitro. In AFG1 -exposed A549 cells, TNF-α-enhanced DNA damage and apoptosis were reversed by CYP2A13 small interfering RNA. Blocking NF-κB pathway inhibited the TNF-α-enhanced CYP2A13 upregulation and DNA damage confirming that the CYP2A13 upregulation by TNF-α plays an essential role in the activation of AFG1 under inflammatory conditions. Taken together, our findings suggest that AFG1 induces TNF-α-dependent lung inflammation, which upregulates CYP2A13 to promote the metabolic activation of AFG1 and enhance oxidative DNA damage in AT-II cells.

Long noncoding RNA TP53TG1 promotes pancreatic ductal adenocarcinoma development by acting as a molecular sponge of microRNA-96.

Long noncoding RNAs (lncRNAs) are emerging as key regulators in cancer initiation and progression. TP53TG1 is a recently identified lncRNA and several studies have shown that TP53TG1 may play the role of tumor suppressor gene or oncogene in different tumors. Nevertheless, the involvement of TP53TG1 in carcinogenesis of pancreatic ductal adenocarcinoma (PDAC) has not been characterized. In our studies, we identified that TP53TG1 was highly expressed in PDAC and was a novel regulator of PDAC development. Knockdown of TP53TG1 inhibited proliferation, induced apoptosis, and decreased migration and invasion in PDAC cells, whereas enhanced expression of TP53TG1 had the opposite effects. Mechanistically, TP53TG1 could directly bind to microRNA (miR)-96 and effectively function as a sponge for miR-96, thus antagonizing the functions of miR-96 and leading to derepression of its endogenous target KRAS, which is a core oncogene in the initiation and maintenance of PDAC. Taken together, these observations imply that TP53TG1 contributes to the growth and progression of PDAC by acting as a competing endogenous RNA (ceRNA) to competitively bind to miR-96 and regulate KRAS expression, which highlights the importance of the complicated miRNA-lncRNA network in modulating the progression of PDAC.