Potential of Targeting TDO2 as the Lung Adenocarcinoma Treatment.

Tryptophan catabolism plays an important role in the metabolic reconnection in cancer cells to support special demands of tumor initiation and progression. The catabolic product of the tryptophan pathway, kynurenine, has the capability of suppressing the immune reactions of tumor cells. In this study, we conducted internal and external cohort studies to reveal the importance of tryptophan 2,3-dioxygenase (TDO) for lung adenocarcinoma (LUAD). Our study further demonstrated that the TDO2 expression was associated with the proliferation, survival, and invasion of LUAD cells, and targeting TDO2 for LUAD tumors could be a potential therapeutic strategy.

Creation of aromatic maize by CRISPR/Cas.

Aroma is an important quality parameter for breeding in rice (Oryza sativa). For example, the aromatic rice varieties basmati and jasmine rice, with a popcorn-like scent, are popular worldwide and routinely command a price premium. 2-acetyl-1-pyrroline (2AP) is a key flavor compound among over 200 volatiles identified in fragrant rice. A naturally fragrant germplasm exists in multiple plant species besides rice, which all exhibit lower activity of BETAINE ALDEHYDE DEHYDROGENASE 2 (BADH2). However, no equivalent aromatic germplasm has been described in maize (Zea mays). Here, we characterized the two maize BADH2 homologs, ZmBADH2a and ZmBADH2b. We generated zmbadh2a and zmbadh2b single mutants and the zmbadh2a-zmbadh2b double mutant by CRISPR/Cas in four inbred lines. A popcorn-like scent was only noticeable in seeds from the double mutant, but not from either single mutant or in wild type. In agreement, we only detected 2AP in fresh kernels and dried mature seeds from the double mutant, which accumulated between 0.028 and 0.723 mg/kg 2AP. These results suggest that ZmBADH2a and ZmBADH2b redundantly participate in 2AP biosynthesis in maize, and represent the creation of the world's first aromatic maize by simultaneous genome editing of the two BADH2 genes.

How does industrial restructuring influence carbon emissions: City-level evidence from China.

This study addresses the question of why industrial restructuring towards light industries or services sometimes fails to achieve carbon emission mitigation goals. By employing a new perspective of dividing industry segments into emission-dominating and non-emission-dominating ones based on Logarithmic Mean Divisia Index (LMDI) decomposition method, this paper analyses city-level carbon dioxide emission reduction performance under three distinctive industrial restructuring directions. Results indicate that carbon dioxide emission dominating segments are relatively fixed across cities, regardless of the various city types in China. The key point to achieve emission reduction through industrial restructuring is to identify and control the emission-dominating segments, instead of economic-leading ones. Besides, emission reduction performance of industrial restructuring from emission-dominating industry segments to services is better than that to non-emission-dominating ones. More importantly, industrial restructuring not involving output scale controlling of emission-dominating segments, or that recklessly rushing towards services are likely to fail the emission mitigation goal. This paper presents a strong international reference that merits cities facing policy hesitation over industrial restructuring directions while in pursuit of emission mitigation. It suggests that cities first focus on identifying the carbon dioxide dominating segments, of which the output scale should be controlled. For cities whose emission-dominating segments are not economic-leading ones, it is necessary to carry out industrial restructuring towards services or non-emission-dominating segments; while for cities heavily dependent on emission-dominating segments, energy efficiency should also be improved.

Emission drivers of cities at different industrialization phases in China.

As cities are the center of human activity and the basic unit of policy design, they have become the focus of carbon dioxide reduction, especially metropolitan areas that are high energy consumers and carbon dioxide emitters in countries such as China. The fact cities differ in their levels of development and stages of industrialization points to the need for tailor-made low-carbon policies. This study is the first to consider cities' different phases of industrialization when analyzing city-level emission patterns and drivers, as well as the decoupling statuses between economic growth and their emission levels in China. The results of 15 representative cities at different phases of industrialization show that various decoupling statuses, driving factors and decoupling efforts exist among cities, and that heterogeneity among these factors also exists among cities at the same industrialization phase. For further decomposition, energy intensity contributed the most to emissions reduction during the period 2005 to 2010, especially for cities with more heavy manufacturing industries, whereas industrial structure was a stronger negative emission driver during the period 2010 to 2015. Based on those findings, we suggest putting into practice a diversified carbon-mitigation policy portfolio according to each city's industrialization phase rather than a single policy that focuses on one specific driving factor. This paper sets an example on emissions-reduction experience for other cities undergoing different industrialization phases in China; it also sheds light on policy initiatives that could be applied to other cities around the world.

Loss of MicroRNA-101 Promotes Epithelial to Mesenchymal Transition in Hepatocytes.

Epithelial-to-mesenchymal transition (EMT) has been implicated in embryonic development and various pathological events. However, the involvement of microRNA in the process of EMT remains to be fully defined in hepatocyte. ZEB1 is a well-known transcriptional repressor of E-cadherin and plays a major role in triggering EMT during organ fibrosis and cancer cell metastasis. Computational microRNA target predictions detect a conserved sequence matching to miR-101 in the 3'UTR of ZEB1 mRNA. Our results confirm that miR-101 suppresses ZEB1 expression by targeting the predicted site of ZEB1 3'UTR. Subsequent investigations show that miR-101 is significantly downregulated in the cultured hepatocytes undergoing EMT and in the hepatocytes isolated from fibrotic liver. Along with the loss of miR-101, the ZEB1 expression increases simultaneously in hepatocytes. In addition, miR-101 levels in HCC cell lines are negatively associated with the ZEB1 productions and the metastatic potentials of tumor cells. Mechanistically, we demonstrate that miR-101 significantly inhibits the TGF-ß1-induced EMT in hepatocytes, whereas inhibition of miR-101 promotes the EMT process as indicated by the changes of morphology, cell migration, and the expression profiles of EMT markers. In the fibrotic liver, ectopic expression of miR-101 can significantly downregulate ZEB1 in the hepatocyte and thereby reduces the mesenchymal marker expression. Moreover, miR-101 significantly inhibits the proliferation and migration of HCC cell. Our results demonstrate that miR-101 regulates HCC cell phenotype by upregulating the epithelial marker genes and suppressing the mesenchymal ones.

MicroRNA-101 suppresses liver fibrosis by targeting the TGFß signalling pathway.

Transforming growth factor-ß (TGFß) is crucial for liver fibrogenesis and the blunting of TGFß signalling in hepatic stellate cells (HSCs) or hepatocytes can effectively inhibit liver fibrosis. microRNAs (miRNAs) have emerged as key regulators in modulating TGFß signalling and liver fibrogenesis. However, the regulation of TGFß receptor I (TßRI) production by miRNA remains poorly understood. Here we demonstrate that the miR-101 family members act as suppressors of TGFß signalling by targeting TßRI and its transcriptional activator Kruppel-like factor 6 (KLF6) during liver fibrogenesis. Using a mouse model of carbon tetrachloride (CCl4 )-induced liver fibrosis, we conducted a time-course experiment and observed significant down-regulation of miR-101 in the fibrotic liver as well as in the activated HSCs and injured hepatocytes in the process of liver fibrosis. Meanwhile, up-regulation of TßRI/KLF6 was observed in the fibrotic liver. Subsequent investigations validated that TßRI and KLF6 were direct targets of miR-101. Lentivirus-mediated ectopic expression of miR-101 in liver greatly reduced CCl4 -induced liver fibrosis, whereas intravenous administration of antisense miR-101 oligonucleotides aggravated hepatic fibrogenesis. Mechanistic studies revealed that miR-101 inhibited profibrogenic TGFß signalling by suppressing TßRI expression in both HSCs and hepatocytes. Additionally, miR-101 promoted the reversal of activated HSCs to a quiescent state, as indicated by suppression of proliferation and migration, loss of activation markers and gain of quiescent HSC-specific markers. In hepatocytes, miR-101 attenuated profibrogenic TGFß signalling and suppressed the consequent up-regulation of profibrogenic cytokines, as well as TGFß-induced hepatocyte apoptosis and the inhibition of cell proliferation. The pleiotropic roles of miR-101 in hepatic fibrogenesis suggest that it could be a potential therapeutic target for liver fibrosis.

Using functional near-infrared spectroscopy to study effects of virtual reality intervention for adolescents with depression in a clinical setting in China: study protocol for a prospective, randomised, controlled trial.

INTRODUCTION: Adolescent depression has been shown to be associated with many devastating psychosocial outcomes. However, there are many barriers that may prevent depressed individuals from receiving specialised treatment. Virtual reality (VR) technology has shown promise as one avenue for overcoming these challenges. This study first aims to evaluate the effectiveness of VR intervention on adolescent depression symptoms, and second, to determine the intervention's underlying mechanism of effect using functional near-infrared spectroscopy (fNIRS). METHODS AND ANALYSIS: This is a single-centre, prospective, randomised controlled clinical trial. Sixty-six eligible adolescents aged 12-18 years with a diagnosis of depression will be randomised in a 1:1 ratio to either the VR treatment group or the conventional treatment group. All patients for both groups will receive usual treatment during a 4-week intervention period. In addition, patients randomised to VR treatment group (n=33) will complete three 20 min VR sessions including attention, executive function and relaxation training per week. Moreover, 33 healthy adolescents will be recruited as the general population. Primary outcome (ie, depressive symptoms) and secondary outcomes (ie, anxiety symptoms, executive function, treatment emergent symptoms, haemoglobin changes measured by fNIRS) will be collected at preintervention, immediately postintervention and at 4 weeks follow-up. The data assessor and analyst will be blinded to group membership. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of Lishui Second People's Hospital. Written informed consent will be obtained for all participants. Results will be disseminated through peer-reviewed journals, national or international conference presentations, media outlets, the internet and various community activities. TRIAL REGISTRATION NUMBER: ChiCTR2300067747.

Blood exosome PD-L1 is associated with PD-L1 expression measured by immunohistochemistry, and lymph node metastasis in lung cancer.

BACKGROUND: Previous observations illustrated that programmed cell death ligand 1 in exosomes (Exo-PD-L1) may lead to immunosuppression. This study proposed to investigate the significance of Exo-PD-L1 and the results of PD-L1 immunohistochemistry (IHC) assay in the clinical diagnosis and treatment of lung cancer. METHODS: 29 lung cancer patients were enrolled. Exosomes were extracted from the blood of patients and purified, and the extracts were identified by Western blot and transmission electron microscope. Next, the levels of Exo-PD-L1 and PD-L1 in tumor tissue were evaluated by enzyme-linked immunosorbent assay (ELISA) and IHC, respectively. The correlation between Exo-PD-L1, IHC PD-L1 status and pathological features of patients was analyzed by applying Chi-square test. After immune checkpoint inhibitor (ICI) treatment, the objective response rate (ORR) was calculated, and drug response prediction in lung cancer patients by using Exo-PD-L1 alone, IHC PD-L1 alone, and their combined detection were analyzed. RESULTS: This study confirmed that lung cancer patients had much expression of PD-L1 in blood exosomes and that Exo-PD-L1 level was associated with IHC PD-L1 status. The expression level of Exo-PD-L1 was evidently related to the positive lymph node metastasis of lung cancer patients, while IHC PD-L1 status was not correlated with clinicopathological features of patients. Moreover, Exo-PD-L1 and IHC PD-L1 alone or their combined detection could be utilized to predict the efficacy of ICI therapy in lung cancer patients. CONCLUSION: The correlation between Exo-PD-L1 and IHC PD-L1 status was indicated, and Exo-PD-L1 could assist in determining the suitable lung cancer patients suitable for ICI therapy using IHC PD-L1. This study provides references for the application of Exo-PD-L1 as an effective predictor of ICI therapy.

Dynamically Expressed miR-BART16 Functions as a Suppressor of CAND1 in Infectious Mononucleosis Caused by Epstein-Barr Virus in Children.

OBJECTIVE: MiR-BART16 is a newly discovered Epstein-Barr Virus-encoded microRNA (miRNA). We aimed to explore the role of EBV-miR-BART16 in infectious mononucleosis (IM). METHODS: Peripheral blood lymphocyte subsets were analyzed in 30 IM and 10 healthy children by flow cytometry. MiR-BART16 and its targets were measured by real-time PCR, western blot, ELISA, and dual-luciferase assay. RESULTS: Serum miR-BART16 expression was significantly higher in the IM children than that in the healthy children, and was positively correlated with EBV copy number. Receiver operating characteristic analysis revealed serum miR-BART16 could differentiate IM and healthy individuals (P=0.0041). CAND1 was targeted and downregulated by miR-BART16 in an EBV infection-dependent way. CONCLUSIONS: These results highlight that EBV-miR-BART16 plays an important role in regulating the expression of CAND1 to affect pediatric IM.

Risk factors analysis of attention deficit/hyperactivity disorder and allergic rhinitis in children: a cross-sectional study.

BACKGROUND: To investigate the relationship between symptom of attention-deficit/hyperactivity disorder (ADHD) and allergic rhinitis (AR) in AR children of different genders and ages. METHODS: Four hundred and sixty-five allergic rhinitis children aged 6-12 years old were recruited in this study. Skin-prick test, Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ), Total Nasal Symptoms Score (TNSS) and the Swanson, Nolan, and Pelham version IV scale (SNAP-IV) were recorded. Patients were divided into AR with ADHD and AR without ADHD, according to the SNAP-IV scale results. RESULTS: Children with the inattention/hyperactivity scale (IHS) > 1.25 accounted for 26.4% of all children with AR. The TNSS with IHS > 1.25 group were significantly higher than the IHS ≤ 1.25 group. Univariate analysis showed that age, gender, duration of AR symptoms, skin index, and PRQLQ subscales were associated with symptoms of hyperactivity and attention deficit (IHS > 1.25). After normalizing the age and gender factors, duration of AR symptoms and skin index correlated with IHS > 1.25. After stratifying age and gender, the correlation between IHS > 1.25 and skin index and PRQLQ subscales was mainly found in male children, and the association between the duration of AR symptoms and IHS > 1.25 was reflected in each group. CONCLUSIONS: ADHD in children with AR is associated with severity, duration, and skin index of AR, and this association is more pronounced in male children.

Prognostic role of haematological indices in sudden sensorineural hearing loss: Review and meta-analysis.

BACKGROUND: Complete blood count (CBC) is an important blood test in clinical practice, and it has been recently used to predict the prognosis of patients with sudden sensorineural hearing loss (SSNHL). Some haematological indices of the CBC test have been reported to be associated with the clinical outcome of SSNHL. However, the prognostic value of these haematological indices in SSNHL is currently under debate. Here, we performed a meta-analysis to investigate the association between haematological indices of the CBC test and clinical outcomes in patients with SSNHL. METHODS: We conducted a meta-analysis of studies that evaluated the association between haematological indices and prognoses in patients with sudden hearing loss. Subgroup and sensitivity analyses were also performed to explore potential sources of heterogeneity. RESULTS: Ten studies that included 972 individuals were identified. Pooled analysis showed neutrophil-to-lymphocyte ratio (NLR) (weighted mean difference [WMD] = -1.69 and p < 0.001), platelet-to-lymphocyte ratio (PLR) (WMD = -38.45 and p < 0.001), neutrophil count (WMD = -1.57 × 109/L and p < 0.001) and lymphocyte count (WMD = 0.41 × 109/L and p < 0.001) to be the factors associated with the prognosis of SSNHL. CONCLUSIONS: Our findings indicated that NLR, PLR, neutrophil count and lymphocyte count are strongly associated with the prognosis of SSNHL. These four indices could be recommended as inexpensive markers to report treatment outcomes.

Association of pediatric allergic rhinitis with the ratings of attention-deficit/hyperactivity disorder.

BACKGROUND: Allergic rhinitis (AR) is currently the most prevalent allergic disease in children and adolescents. OBJECTIVE: Surveys conducted by population-based studies of East Asia revealed an increased prevalence of behavioral disorders in patients with AR. Thus, in this study, we explored the prevalence of attention-deficit/hyperactivity disorder (ADHD) in pediatric patients with AR. METHODS: A total of 333 children (6-12 years of age) with AR and a total of 322 age-matched controls were included in this study. An otorhinolaryngologist diagnosed all AR cases and evaluated the severity of the disease. Skin-prick test results for 18 major allergens, Paediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ), Child Behavior Checklist (CBCL), and Swanson, Nolan, and Pelham version IV (SNAP-IV) scores were recorded. RESULTS: In total, 320 age-matched controls and 323 children with AR completed the study. With respect to the Total Nasal Symptom Score and the PRQLQ, the condition of the experimental group was more serious than that of the controls. The scores on the hyperactivity/impulsivity and inattention subscales, which evaluate ADHD symptoms, and those on the CBCL subscales were significantly higher in patients with AR than in the controls (all p values were <0.01). From the results of the Pearson correlation, we deduced that there were significant positive correlations between the AR-related data and each subscale of the CBCL and SNAP-IV in the AR group. Moreover, two basic characteristics (males and environmental exposure to tobacco smoke) present significant positive and age showed a significant negative correlations affect ADHD symptom in both the AR group and the control group. Also, in the "pure AR" group, hierarchical regression analyses were performed to determine the subtests of the PRQLQ, which are significant predictors of SNAP-IV and CBCL. CONCLUSIONS: Apart from AR per se, the possible comorbidities of impulsivity and inattention are important when managing children with AR. It is essential to evaluate the symptoms of ADHD in children and adolescents with AR.

TGF-ß-induced hepatocyte lincRNA-p21 contributes to liver fibrosis in mice.

Hepatocyte death, as well as the following inflammatory and fibrogenic signaling cascades, is the key trigger of liver fibrosis. Here, we isolated hepatocytes from CCl4-induced fibrotic liver and found that hepatocyte lincRNA-p21 significantly increased during liver fibrosis. The increase of hepatocyte lincRNA-p21 was associated with the loss of miR-30, which can inhibit TGF-ß signaling by targeting KLF11. We revealed that lincRNA-p21 modulated miR-30 availability by acting as a competing endogenous RNA (ceRNA). The physiological significance of this interaction is highlighted by the feedback loop, in which lincRNA-p21 works as a downstream effector of the TGF-ß signaling to strengthen TGF-ß signaling and mediate its role in promoting liver fibrosis by interacting with miR-30. In vivo results showed that knockdown of hepatocyte lincRNA-p21 greatly reduced CCl4-induced liver fibrosis and inflammation, whereas ectopic expression of miR-30 in hepatocyte exhibited the similar results. Mechanistic studies further revealed that inhibition of miR-30 impaired the effects of lincRNA-p21 on liver fibrosis. Additionally, lincRNA-p21 promoted hepatocyte apoptosis in vitro and in vivo, whereas the proliferation rate of hepatocyte was suppressed by lincRNA-p21. The pleiotropic roles of hepatocyte lincRNA-p21 suggest that it may represent an unknown paradigm in liver fibrosis and serve as a potential target for therapy.

MicroRNA-30 Protects Against Carbon Tetrachloride-induced Liver Fibrosis by Attenuating Transforming Growth Factor Beta Signaling in Hepatic Stellate Cells.

Transforming growth factor beta (TGF-ß) is crucial for transdifferentiation of hepatic stellate cells (HSCs) and the blunting of TGF-ß signaling in HSCs can effectively prevent liver fibrosis. Krüppel-like factor 11 (KLF11) is an early response transcription factor that potentiates TGF-ß/Smad signaling by suppressing the transcription of inhibitory Smad7. Using a mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis, we observed significant upregulation of KLF11 in the activated HSCs during liver fibrogenesis. Meanwhile, the downregulation of miR-30 was observed in the HSCs isolated from fibrotic liver. Adenovirus-mediated ectopic expression of miR-30 was under the control of smooth muscle α-actin promoter, showing that the increase in miR-30 in HSC greatly reduced CCl4-induced liver fibrosis. Subsequent investigations showed that miR-30 suppressed KLF11 expression in HSC and led to a significant upregulation of Smad7 in vivo. Mechanistic studies further confirmed that KLF11 was the direct target of miR-30, and revealed that miR-30 blunted the profibrogenic TGF-ß signaling in HSC by suppressing KLF11 expression and thus enhanced the negative feedback loop of TGF-ß signaling imposed by Smad7. Finally, we demonstrated that miR-30 facilitated the reversal of activated HSC to a quiescent state as indicated by the inhibition of proliferation and migration, the loss of activation markers, and the gain of quiescent HSC markers. In conclusion, our results define miR-30 as a crucial suppressor of TGF-ß signaling in HSCs activation and provide useful insights into the mechanisms underlying liver fibrosis.