Automated and fast online method for simultaneously determining a broad spectrum of per- and polyfluoroalkyl substances in a small volume of cerebrospinal fluid.

Per- and polyfluoroalkyl substances (PFASs) are potentially neurotoxic compounds. Levels of PFASs in cerebrospinal fluid (CSF) could directly reflect their potential harm to the central nervous system. Because of the variety of PFASs and the rarity of CSF, there is an urgent need to establish a rapid online method to detect a broad spectrum of PFASs accurately and simultaneously by consuming a small amount of CSF. In this study, we developed a fast and automated method to analyze 52 PFASs in human CSF samples using online TurboFlow ultra-high-performance liquid chromatography-tandem mass spectrometry. Our method offered excellent matrix-matched standard curve linearity (correlation coefficient > 0.99), good limits of quantitation (MLOQs) (0.01 to 0.08 ng mL-1), satisfactory accuracy (recoveries of 74.6%-119.1%) and precision (relative standard deviations of 1.4%-13.2%), small sample amount consumption (50 µL), and fast analysis time (18 min per sample) without complex sample pretreatment procedures. These are advantageous for the high throughput screening of PFASs in environmental epidemiology studies. Repeated freeze-thaw experiments showed that it was better to perform the analytical process soon as possible after sample collection. The established method was used to analyze PFASs in 60 people. Short-chain PFASs, perfluorobutanoic acid (PFBA), perfluoropentanoic acid (PFPeA), and novel PFASs [sodium 2-(N-ethylperfluorooctane-1-sulfonamido)ethyl phosphate (SAmPAP), perfluoroethylcyclohexanesulfonate (PFECHS), and perfluoro-3, 7-dimethyloctanoic acid (P37DMOA)] were reported in CSF for the first time. PFBA and PFPeA were detected in all samples with mean concentrations of 0.24 and 0.22 ng mL-1, respectively. We also calculated the blood-brain barrier transmission efficiency of PFASs (RPFAS), and the mean RPFBA value was above 1, which indicated that PFBA might transfer from serum to CSF.

Wearing individualized 3D printed oral stent to protect normal tissues in patients with nasopharyngeal carcinoma during radiotherapy.

PURPOSE: To demonstrate a new individualized 3D printed oral stent in radiotherapy of nasopharyngeal carcinoma (NPC) patients and carry out a comparative analysis combining with clinical case. MATERIAL AND METHODS: Thirty NPC patients treated in our institution from September 2021 to October 2022 were prospectively enrolled. An individualized 3D printed oral stent was designed for each patient, and one set of computed tomography (CT) slices were obtained with /without wearing the oral stent, respectively. After delineation of target volumes and organs at risk (OARs) on the two CT slices, we finished two treatment plans by using the same target objectives, critical constraints and plan setup for each patient. Finally, the dose distribution and other dosimetric parameters of target volumes and OARs between the two plans were compared. RESULTS: Tongue volume and tongue length outside of mouth was 10.4 ± 2.5 cm3 and 2.8 ± 0.6 cm, respectively, distance between dorsal surface of oral tongue and plate increased from 0.3 ± 0.3 cm to 2.2 ± 0.5 cm by wearing the oral stent. For the target volume, there was no significant difference. However, Dmax of tongue, tongue tip and periglottis decreased significantly from 6352.6 ± 259.9 cGy to 5994.9 ± 478.9 cGy, 3499.8 ± 250.6 cGy to 3357.7 ± 158.0 cGy and 6345.5 ± 171.0 cGy to 6133.4 ± 263.3 cGy, respectively (p = 0.000); Dmean of tongue, tongue tip and periglottis decreased significantly from 3714.7 ± 204.2 cGy to 3169.7 ± 200.9 cGy, 3060.8 ± 216.2 cGy to 2509.6 ± 196.7 cGy and 3853.3 ± 224.9 cGy to 3079.3 ± 222.0 cGy, respectively (p = 0.000). CONCLUSION: The individualized 3D printed oral stent can reduce the dose of oral tissues and organs, so as to reduce the oral adverse reactions and improve the compliance of patients and the quality of their life. The technique can be used in radiotherapy of NPC patients.

HACE1 negatively regulates neuroinflammation through ubiquitylating and degrading Rac1 in Parkinson's disease models.

Neuroinflammation plays an important role in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease. HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) is a tumor suppressor. Recent evidence suggests that HACE1 may be involved in oxidative stress responses. Due to the critical role of ROS in neuroinflammation, we speculated that HACE1 might participate in neuroinflammation and related neurodegenerative diseases, such as PD. In this study, we investigated the role of HACE1 in neuroinflammation of PD models. We showed that HACE1 knockdown exacerbated LPS-induced neuroinflammation in BV2 microglial cells in vitro through suppressing ubiquitination and degradation of activated Rac1, an NADPH oxidase subunit. Furthermore, we showed that HACE1 exerted vital neuronal protection through increasing Rac1 activity and stability in LPS-treated SH-SY5Y cells, as HACE1 knockdown leading to lower tolerance to LPS challenge. In MPTP-induced acute PD mouse model, HACE1 knockdown exacerbated motor deficits by activating Rac1. Finally, mutant α-synuclein (A53T)-overexpressing mice, a chronic PD mouse model, exhibited age-dependent reduction of HACE1 levels in the midbrain and striatum, implicating that HACE1 participated in PD pathological progression. This study for the first time demonstrates that HACE1 is a negative regulator of neuroinflammation and involved in the PD pathogenesis by regulating Rac1 activity. The data support HACE1 as a potential target for PD and other neurodegenerative diseases.

PTPN1/2-mediated dephosphorylation of MITA/STING promotes its 20S proteasomal degradation and attenuates innate antiviral response.

Upon cytosolic viral DNA stimulation, cGMP-AMP synthase (cGAS) catalyzes synthesis of 2'3'cGMP-AMP (cGAMP), which binds to the adaptor protein MITA (mediator of IRF3 activation, also called STING, stimulator of IFN genes) and induces innate antiviral response. How the activity of MITA/STING is regulated to avoid excessive innate immune response is not fully understood. Here we identified the tyrosine-protein phosphatase nonreceptor type (PTPN) 1 and 2 as MITA/STING-associated proteins. PTPN1 and PTPN2 are associated with MITA/STING following viral infection and dephosphorylate MITA/STING at Y245. Dephosphorylation of MITA/STING leads to its degradation via the ubiquitin-independent 20S proteasomal pathway, which is dependent on the intrinsically disordered region (IDR) of MITA/STING. Deficiencies of PTPN1 and PTPN2 enhance viral DNA-induced transcription of downstream antiviral genes and innate antiviral response. Our findings reveal that PTPN1/2-mediated dephosphorylation of MITA/STING and its degradation by the 20S proteasomal pathway is an important regulatory mechanism of innate immune response to DNA virus.

Global proteome response to Pb(II) toxicity in poplar using SWATH-MS-based quantitative proteomics investigation.

Lead (Pb) toxicity is a growing serious environmental pollution that threatens human health and crop productivity. Poplar, as an important economic and ecological forest species, has the characteristics of fasting growth and accumulating heavy metals, which is a powerful model plant for phytoremediation. Here, a novel label-free quantitative proteomic platform of SWATH-MS was applied to detect proteome changes in poplar seedling roots following Pb treatment. In total 4388 unique proteins were identified and quantified, among which 542 proteins showed significant abundance changes upon Pb(II) exposure. Functional categorizations revealed that differentially expressed proteins (DEPs) primarily distributed in specialized biological processes. Particularly, lignin and flavonoid biosynthesis pathway were strongly activated upon Pb exposure, implicating their potential roles for Pb detoxification in poplar. Furthermore, hemicellulose and pectin related cell wall proteins exhibited increased abundances, where may function as a sequestration reservoir to reduce Pb toxicity in cytoplasm. Simultaneously, up-regulation of glutathione metabolism may serve as a protective role for Pb-induced oxidative damages in poplar. Further correlation investigation revealed an extra layer of post-transcriptional regulation during Pb response in poplar. Overall, our work represents multiply potential regulators in mediating Pb tolerance in poplar, providing molecular targets and strategies for phytoremediation.

Development and validation of a 10-gene prognostic signature for acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is the most common type of adult acute leukaemia and has a poor prognosis. Thus, optimal risk stratification is of greatest importance for reasonable choice of treatment and prognostic evaluation. For our study, a total of 1707 samples of AML patients from three public databases were divided into meta-training, meta-testing and validation sets. The meta-training set was used to build risk prediction model, and the other four data sets were employed for validation. By log-rank test and univariate COX regression analysis as well as LASSO-COX, AML patients were divided into high-risk and low-risk groups based on AML risk score (AMLRS) which was constituted by 10 survival-related genes. In meta-training, meta-testing and validation sets, the patient in the low-risk group all had a significantly longer OS (overall survival) than those in the high-risk group (P < .001), and the area under ROC curve (AUC) by time-dependent ROC was 0.5854-0.7905 for 1 year, 0.6652-0.8066 for 3 years and 0.6622-0.8034 for 5 years. Multivariate COX regression analysis indicated that AMLRS was an independent prognostic factor in four data sets. Nomogram combining the AMLRS and two clinical parameters performed well in predicting 1-year, 3-year and 5-year OS. Finally, we created a web-based prognostic model to predict the prognosis of AML patients (https://tcgi.shinyapps.io/amlrs_nomogram/).

Transcription factor RUNX3 promotes CD8+ T cell recruitment by CCL3 and CCL20 in lung adenocarcinoma immune microenvironment.

Considering the existence of immune-desert in tumor microenvironment, the clinical efficacy of immunotherapy for lung adenocarcinoma is limited. This study aims to investigate the ability of transcription factors in regulating tumor immune microenvironment in lung adenocarcinoma. RNA-seq data were collected from the The Cancer Genome Atlas database. The relationships between transcription factors and immune infiltrates were assessed. Runt-related transcription factor 3 (RUNX3)-associated immune pathways were investigated by the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and Gene set enrichment analysis. Upregulated chemokines in the RUNX3-overexpressed cell line were determined by quantitative real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay. These chemokines were further confirmed in RUNX3-downregulated cell lines. Immunochemistry was conducted to determine the expression of RUNX3, CCL3, CCL20, and the numbers of CD8+ T lymphocytes in human lung cancer tissues. Chemokine receptors in CD8+ T cells were explored by flow cytometry and immunofluorescence. T cell recruitment was investigated by transwell assay. After screening 406 transcription factors, RUNX3 was found strongly correlated T cells, cytotoxic lymphocytes, and CD8+ T cells. RUNX3 was associated with a variety of immunomodulators, including LAG3, CTLA-4, PD-1, and TIGIT. More importantly, RUNX3 was involved in immune-related pathways, especially immune cell migration-related pathways. Further investigation exhibited RUNX3 could upregulate CCL3 and CCL20 whose receptors CCR5 and CCR6 were upregulated in CD8+ effector T cells, while downregulation of RUNX3 decreased the expression of CCL3 and CCL20 and the infiltration of CD8+ T cells in RUNX3-downregulated lung cancer cell lines. Immunochemistry exhibited positive correlations of RUNX3 with CCL3 and CD8+ T cells in clinical lung adenocarcinoma samples. The chemotaxis assay proved RUNX3 could promote CD8+ T cell recruitment by upregulating CCL3 and CCL20. This study unearths RUNX3 related molecular mechanisms of tumor immune microenvironment and may reverse the immune-desert condition in lung adenocarcinoma and be combined with immune checkpoint blockade and adoptive cell therapy.

Diverse function and regulation of CmSnf1 in entomopathogenic fungus Cordyceps militaris.

SNF1/AMPK protein kinases play important roles in fungal development and activation of catabolite-repressed genes. In this study, we characterized the role of SNF1 ortholog in Cordyceps militaris (CmSnf1). The vegetative growth of a CmSnf1 deletion mutant was (ΔCmSnf1) reduced by 42.2% with arabinose as a sole carbon source. Most strikingly, the ΔCmSnf1 produced only a few conidia and exhibited delayed conidial germination. We found that CmSnf1 was necessary for mycelium to penetrate the insect cuticle to form the fruiting body on silkworm pupae, consistent with the down-regulation of chitinase- and protease-encoding genes in ΔCmSnf1. However, cordycepin content increased by more than 7 times in culture supernatants. Correspondingly, the relative expression levels of cordycepin gene cluster members were also elevated. In particular, the expression of cns4 associated with cordycepin transfer was up-regulated >10-fold. Furthermore, transcriptional analysis showed that CmSnf1 regulated the expression of genes involved in cell autophagy and oxidative stress tolerance. We speculated that under environmental stress, both the ATG and SNF1 pathways might collaborate to sustain adverse environments. Our study provides an initial framework to probe the diverse function and regulation of CmSnf1 in C. militaris, which will shed more light on the direction of molecular improvement of medicinal fungi.

ECCDIA: an interactive web tool for the comprehensive analysis of clinical and survival data of esophageal cancer patients.

BACKGROUND: Esophageal cancer (EC) is considered as one of the deadliest malignancies with respect to incidence and mortality rate, and numerous risk factors may affect the prognosis of EC patients. For better understanding of the risk factors associated with the onset and prognosis of this malignancy, we develop an interactive web-based tool for the convenient analysis of clinical and survival characteristics of EC patients. METHODS: The clinical data were obtained from The Surveillance, Epidemiology, and End Results (SEER) database. Seven analysis and visualization modules were built with Shiny. RESULTS: The Esophageal Cancer Clinical Data Interactive Analysis (ECCDIA, http://webapps.3steps.cn/ECCDIA/ ) was developed to provide basic data analysis, visualization, survival analysis, and nomogram of the overall group and subgroups of 77,273 EC patients recorded in SEER. The basic data analysis modules contained distribution analysis of clinical factor ratios, Sankey plot analysis for relationships between clinical factors, and a map for visualizing the distribution of clinical factors. The survival analysis included Kaplan-Meier (K-M) analysis and Cox analysis for different subgroups of EC patients. The nomogram module enabled clinicians to precisely predict the survival probability of different subgroups of EC patients. CONCLUSION: ECCDIA provides clinicians with an interactive prediction and visualization tool for visualizing invaluable clinical and prognostic information of individual EC patients, further providing useful information for better understanding of esophageal cancer.

Clinical Features of Chinese Sporadic Leber Hereditary Optic Neuropathy Caused by Rare Primary mtDNA Mutations.

OBJECTIVE: The primary aim of this study was to describe clinical features of Chinese sporadic Leber hereditary optic neuropathy (LHON) caused by rare primary mitochondrial DNA (mtDNA) mutations. METHODS: We characterized a Chinese patient cohort with rare primary mtDNA mutations at Beijing Tongren Hospital between 2015 and 2018. The clinical features of these patients were retrospectively recorded and analyzed. RESULTS: Sixteen patients with LHON who had the selected rare primary mutations, including m.4171C>A (3 patients), m.10197G>A (1 patient), m.14459G>A (4 patients), and m.14502T>C (8 patients), were evaluated. The mean age at disease onset was 15 ± 6 years, and the male to female ratio was 15:1. Of 32 eyes of all patients, 75% (24/32) had a worst Snellen best-corrected visual acuity ≤0.1 (worse than 20/200), while 67% (2/3) who were carrying the m.4171C>A mutation experienced significant visual improvement. In addition, 40% (2/5) of patients with LHON carrying only m.14502T>C mutation had only mild visual impairment. Isolated manifestations of LHON was present in 94% (15/16) of all patients; 1 patient with the m.14459G>A mutation had LHON plus dystonia. Brain MRI T2 short tau inversion recovery sequences demonstrated optic atrophy in 62.5% (10/16); increased T2 signal in the optic nerve was found in 38% (6/16) of patients. The patient with LHON plus dystonia demonstrated optic atrophy and increased T2 signal in basal ganglia. CONCLUSION: Patients with LHON and rare primary mutations have diverse clinical phenotypes. Those with the m.4171C>A mutation are more likely to have a good visual prognosis, while the m.14502T>C mutation may play a synergistic role in disease onset. Increased signal in the optic nerve on MRI is not rare, and this feature should not exclude LHON as the potential cause for optic neuropathy.

A technique to reduce skin toxicity in radiotherapy treatment planning for esophageal cancer.

PURPOSE: To demonstrate a specific skin dose limiting technique in radiotherapy treatment planning for esophageal cancer and carry out a comparative analysis combining with clinical cases. MATERIAL AND METHODS: Thirty patients with cervical and upper thoracic esophageal carcinoma previously treated in our institution were selected. A treatment plan had been finished previously according to the planning parameters directives from physician and delivered for each patient. In this study, we copied the previously delivered plans in radiotherapy treatment planning system and converted a low dose level (usually 5Gy) to a skin dose limiting structure (SDLS), then we set the objective functions of the SDLS in the Pinnacle Inverse Planning module and re-optimize the plans to reduce the skin doses. Finally, we compared the dose distribution and other parameters of target volume and organs at risk (OARs) between the old plans and the new plans. RESULTS: There was no significant difference in most of OARs sparing. However, for all plans, the maximum dose to the SDLS decreased from 6145.90 ± 416.96 cGy to 5562.09 ± 616.69 cGy with maximum difference of 1361.30 cGy (P < 0.05), the percentage volume of 40Gy received by the SDLS decreased from (10.20 ± 6.36)% to (5.46 ± 4084)% with maximum difference of 9.89% (P < 0.05). For the target volume, there was no significant difference in the average dose and maximum dose, the approximate minimum dose to the target volume decreased from 5711.28 ± 164.61 cGy to 5584.93 ± 157.70 cGy (P < 0.05), the conformal index and homogeneity index of the target volume were hardly changed. CONCLUSION: In radiotherapy treatment planning for esophageal cancer patients, the skin dose can be significantly reduced using the skin dose limiting technique, and the impact on the dose to target volume and OARs is little, this technique can be used in most radiotherapy treatment planning.

PCA via joint graph Laplacian and sparse constraint: Identification of differentially expressed genes and sample clustering on gene expression data.

BACKGROUND: In recent years, identification of differentially expressed genes and sample clustering have become hot topics in bioinformatics. Principal Component Analysis (PCA) is a widely used method in gene expression data. However, it has two limitations: first, the geometric structure hidden in data, e.g., pair-wise distance between data points, have not been explored. This information can facilitate sample clustering; second, the Principal Components (PCs) determined by PCA are dense, leading to hard interpretation. However, only a few of genes are related to the cancer. It is of great significance for the early diagnosis and treatment of cancer to identify a handful of the differentially expressed genes and find new cancer biomarkers. RESULTS: In this study, a new method gLSPCA is proposed to integrate both graph Laplacian and sparse constraint into PCA. gLSPCA on the one hand improves the clustering accuracy by exploring the internal geometric structure of the data, on the other hand identifies differentially expressed genes by imposing a sparsity constraint on the PCs. CONCLUSIONS: Experiments of gLSPCA and its comparison with existing methods, including Z-SPCA, GPower, PathSPCA, SPCArt, gLPCA, are performed on real datasets of both pancreatic cancer (PAAD) and head & neck squamous carcinoma (HNSC). The results demonstrate that gLSPCA is effective in identifying differentially expressed genes and sample clustering. In addition, the applications of gLSPCA on these datasets provide several new clues for the exploration of causative factors of PAAD and HNSC.

Pseudogene CHIAP2 inhibits proliferation and invasion of lung adenocarcinoma cells by means of the WNT pathway.

Recently, pseudogenes have emerged as critical regulators in the onset of human neoplasia. Here, we present a comprehensive analysis of pseudogene alterations at transcriptional levels in lung adenocarcinoma (LUAD) from The Cancer Genome Atlas. By combinations of differential expression analysis, survival analysis, and univariate and multivariable Cox proportional hazards regression models, we identified four dysregulated pseudogenes, whose expression level was closely related to LUAD patients' prognosis and the four pseudogene signature could act as an independent prognostic indicator for LUAD patients. We further characterized CHIAP2, one of those four pseudogenes, whose expression level was the most closely linked to LUAD patients' prognosis. Consistent with our analysis, the expression of CHIAP2 was abnormally downregulated in LUAD tissues compared with that in normal tissues in our 50 pairs of clinical samples. Functional assays demonstrated that upregulation of CHIAP2 significantly impaired cell proliferation and invasion. After performing RNA sequencing (RNA-seq) and small RNA-seq between CHIAP2 overexpression and negative control LUAD cell lines, we identified differentially expressed messenger RNAs and microRNAs (miRNAs), among which six miRNAs were downregulated. Target genes of six downregulated miRNAs were predicted with online miRNA target prediction tools and significant pathways including the WNT signal pathway were identified with Gene Set Enrichment Analysis. By combining predictor genes of six downregulated miRNAs and dysregulated genes of the WNT pathway, we inferred that overexpression of CHAP2 may inhibit LUAD cell proliferation and invasion via modulation of NFATC2 or GSK3B (WNT signal pathway) targeted by miR-3614-5p or miR-873-3p.

Identification of an immune signature predicting prognosis risk of patients in lung adenocarcinoma.

BACKGROUND: Lung cancer has become the most common cancer type and caused the most cancer deaths. Lung adenocarcinoma (LUAD) is one of the major type of lung cancer. This study aimed to establish a signature based on immune related genes that can predict patients' OS for LUAD. METHODS: The expression data of 976 LUAD patients from The Cancer Genome Atlas database (training set) and the Gene Expression Omnibus database (four testing sets) and 1534 immune related genes from the ImmPort database were used for generation and validation of the signature. The glmnet Cox proportional hazards model was used to find the best gene model and construct the signature. To assess the independently prognostic ability of the signature, the Kaplan-Meier survival analysis and Cox's proportional hazards model were performed. RESULTS: A gene model consisting of 30 immune related genes with the highest frequency after 1000 iterations was used as our signature. The signature demonstrated robust prognostic ability in both training set and testing set and could serve as an independent predictor for LUAD patients in all datasets except GSE31210. Besides, the signature could predict the overall survival (OS) of LUAD patients in different subgroups. And this signature was strongly associated with important clinicopathological factors like recurrence and TNM stage. More importantly, patients with high risk score presented high tumor mutation burden. CONCLUSIONS: This signature could predict prognosis and reflect the tumor immune microenvironment of LUAD patients, which can promote individualized treatment and provide potential novel targets for immunotherapy.

MicroRNA-302d promotes the proliferation of human pluripotent stem cell-derived cardiomyocytes by inhibiting LATS2 in the Hippo pathway.

Recent evidence has shown that cardiomyocytes (CMs) can proliferate at a low level after myocardial infarction (MI), but it is insufficient to reestablish heart function. Several microRNAs (miRNAs) have been proven to sufficiently induce rodent CM proliferation. However, whether miRNAs identified in rodents can promote human CM proliferation is unknown due to the poorly conserved functions of miRNAs among species. In the present study, we demonstrate that i) expression of microRNA-302d (miR-302d) decreased significantly during CM differentiation from human pluripotent stem cells (hPSCs) from day 4 to day 18; ii) miR-302d efficiently promoted proliferation of hPSC-derived CMs; iii) miR-302d promoted CM proliferation by targeting LATS2 in the Hippo pathway; and iv) RNA-sequencing analysis revealed that overexpression of miR-302d induced changes in gene expression, which mainly converged on the cell cycle. Our study provides further evidence for the therapeutic potential of miR-302d.

Clinical outcomes of botulinum toxin A management for neurogenic detrusor overactivity: meta-analysis.

The aim of this work was to evaluate the efficacy and safety of botulinum toxin A (BTX-A) treatment in patients with neurogenic detrusor overactivity. PUBMED, EMBASE, and Cochrane Library were identified on 13 May 2017 to identify relevant randomized controlled trials. All data obtained were analyzed using Stata 12.0. Five randomized controlled trials were included in this study. Compared to placebo, the BTX-A groups had significantly fewer urinary incontinence (UI) episodes per day and per week (BTX-A with 300 U for frequency of UI per day at week 2, mean difference (MD): -1.13, 95% confidence interval (CI): -1.89 to -0.37; 200 U; BTX-A with 300 U for frequency of UI per week at week 6, MD: -11.42, 95% CI: -13.91 to -8.93; BTX-A with 200 U for frequency of UI per week at week 6, MD: -10.72, 95% CI: -13.40 to -8.04), increased in maximum cystometric capacity at week 6 (BTX-A with 300 U, MD: 154.88, 95% CI: 133.92-175.84; BTX-A with 200 U, MD: 141.30, 95% CI: 121.28-161.33), decreased maximum detrusor pressure at week 6 (BTX-A with 300 U, MD: -31.72, 95% CI: -37.69 to -25.75; BTX-A with 200 U, MD: -33.47, 95% CI: -39.20 to -27.73). For adverse effects, BTX-A was often associated with more complications and urinary tract infections (BTX-A with 300 U: relative risk (RR):1.42, 95% CI: 1.15-1.76; BTX-A with 200 U: RR: 1.42, 95% CI: 1.11-1.82). This meta-analysis suggests that treatment with BTX-A is effective and safe for neurogenic detrusor overactivity, and recommends using BTX-A with 300 U or with 200 U, as suitable dosage.

Quantitative Proteomics Identified TTC4 as a TBK1 Interactor and a Positive Regulator of SeV-Induced Innate Immunity.

TBK1, STING, and MDA5 are important players within the antiviral innate immune response network. We mapped the interactome of endogenous TBK1, STING, and MDA5 by affinity enrichment MS in virally infected or uninfected THP-1 cells. Based on quantitative data of more than 2000 proteins and stringent statistical analysis, 58 proteins were identified as high-confidence interactors for at least one of three bait proteins. Our data indicated that TBK1 and MDA5 mostly interacted within preexisting protein networks, while STING interacted with different proteins with different viral infections. Functional analysis was performed on 17 interactors, and six were found to have functions in innate immune responses. We identified TTC4 as a TBK1 interactor and positive regulator of sendai virus-induced innate immunity.

Population admixture can enhance establishment success of the introduced biological control agent Cryptolaemus montrouzieri.

BACKGROUND: Introduced biological control agents have opportunities of population admixture through multiple introductions in the field. However, the importance of population admixture for their establishment success often remains unclear. Previous studies based on genetic markers have suggested a history of population admixture in the predatory ladybird Cryptolaemus montrouzieri Mulsant in China. RESULTS: We tested whether population admixture may lead to fitness changes under laboratory conditions. We first found no mating barrier or strong bias between two parental populations, despite their differences in genetics and phenotypes. Then, our experimental evidence supported the hypothesis that admixed populations have a higher potential of establishment success, due to their superior reproductive ability, and hunger and cold tolerance inherited from one of the parental populations. CONCLUSIONS: We suggest that population admixture can be a breeding method to improve the performance of biological control agents, particularly when used in a classical biological control approach, but that consequences for potential invasiveness need to be considered.

Analysis of PD-1 related immune transcriptional profile in different cancer types.

BACKGROUND: Programmed cell death 1 (PD-1) functions as an immune checkpoint in the process of anti-tumor immune response. The PD-1 blockade is now becoming a fundamental part in cancer immunotherapy. So it's essential to elicit the PD-1 related immune process in different types of cancer. METHODS: The Cancer Genome Atlas was used to collect the RNA-seq data of 33 cancer types. The microenvironment cell populations-counter was used to analyze the immune cell infiltrates. KEGG and GO analysis were performed to investigate PD-1 associated biological process. Kaplan-Meier survival curves and Cox's proportional hazards model were performed for prognostic value analysis. RESULTS: We demonstrated that PD-1 expression varied in different cancer types. The uveal melanoma had a low PD-1 expression and poor infiltrated with immune cells. But it showed the strong correlation of PD-1 with the most types of immune cells. The PD-1 demonstrated a robust relationship with other immunomodulators and showed its involvement in critical functions correlated with anti-tumor immune pathways. Survival analysis indicated the PD-1 expression suggested different prognosis in different cancer types. CONCLUSIONS: Our investigations promote a better understanding of the PD-1 blockade and provide PD-1 related personized combined immunotherapy for different types of cancer patients.

Cheminformatic Insight into the Differences between Terrestrial and Marine Originated Natural Products.

This is a new golden age for drug discovery based on natural products derived from both marine and terrestrial sources. Herein, a straightforward but important question is "what are the major structural differences between marine natural products (MNPs) and terrestrial natural products (TNPs)?" To answer this question, we analyzed the important physicochemical properties, structural features, and drug-likeness of the two types of natural products and discussed their differences from the perspective of evolution. In general, MNPs have lower solubility and are often larger than TNPs. On average, particularly from the perspective of unique fragments and scaffolds, MNPs usually possess more long chains and large rings, especially 8- to 10-membered rings. MNPs also have more nitrogen atoms and halogens, notably bromines, and fewer oxygen atoms, suggesting that MNPs may be synthesized by more diverse biosynthetic pathways than TNPs. Analysis of the frequently occurring Murcko frameworks in MNPs and TNPS also reveals a striking difference between MNPs and TNPs. The scaffolds of the former tend to be longer and often contain ester bonds connected to 10-membered rings, while the scaffolds of the latter tend to be shorter and often bear more stable ring systems and bond types. Besides, the prediction from the naïve Bayesian drug-likeness classification model suggests that most compounds in MNPs and TNPs are drug-like, although MNPs are slightly more drug-like than TNPs. We believe that MNPs and TNPs with novel drug-like scaffolds have great potential to be drug leads or drug candidates in drug discovery campaigns.