Liver Immune Profiling Reveals Pathogenesis and Therapeutics for Biliary Atresia.

Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1+effector T and natural killer (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did not cease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumulation in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation ameliorated liver damage. In a pilot clinical study, we demonstrated that rituximab was effective in depleting hepatic B cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those of control subjects. In summary, our comprehensive immune profiling in infants with BA had educed that B-cell-modifying therapies may alleviate liver pathology.

Succinate and inosine coordinate innate immune response to bacterial infection.

Macrophages restrict bacterial infection partly by stimulating phagocytosis and partly by stimulating release of cytokines and complement components. Here, we treat macrophages with LPS and a bacterial pathogen, and demonstrate that expression of cytokine IL-1ß and bacterial phagocytosis increase to a transient peak 8 to 12 h post-treatment, while expression of complement component 3 (C3) continues to rise for 24 h post-treatment. Metabolomic analysis suggests a correlation between the cellular concentrations of succinate and IL-1ß and of inosine and C3. This may involve a regulatory feedback mechanism, whereby succinate stimulates and inosine inhibits HIF-1α through their competitive interactions with prolyl hydroxylase. Furthermore, increased level of inosine in LPS-stimulated macrophages is linked to accumulation of adenosine monophosphate and that exogenous inosine improves the survival of bacterial pathogen-infected mice and tilapia. The implications of these data suggests potential therapeutic tools to prevent, manage or treat bacterial infections.

Engrailed 2 triggers the activation of multiple phosphorylation-induced signaling pathways in both transcription-dependent and -independent manners.

Homeodomain (HD)-containing proteins are typically recognized as transcription factors. Engrailed 2 (EN2) is an HD-containing protein that is highly expressed in various types of cancers, however, the mechanism underlying the biological function of EN2 is not fully understood. Here, we report a transcription-independent function of EN2 in addition to its role as a transcription factor. EN2 expression leads to the activation of multiple signaling pathways mediated by phosphorylation cascades. A phosphoproteomic analysis revealed that the phosphorylation status of numerous protein sites was altered after EN2 is expressed. Notably, EN2 was shown to interact with a myriad of proteins implicated in phosphorylation signaling cascades, as determined by immunoprecipitation-mass spectrometry (IP-MS). We validated the interaction between EN2 and B55α, the regulatory subunit of the PP2A-B55α complex, and confirmed that the phosphatase activity of the complex was suppressed by EN2 binding. To target EN2-induced malignancy, two kinds of small molecules were utilized to inhibit the EN2-activated NF-κB and AKT signaling pathways. A clear synergistic effect was observed when the activation of the two pathways was simultaneously blocked. Collectively, the data show that EN2 functions in a transcription-independent manner in addition to its role as a transcription factor. This finding may have therapeutic implications in treating esophageal squamous cell carcinoma (ESCC).

Association study for the role of MMP8 gene polymorphisms in Colorectal cancer susceptibility.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant tumors, influenced by several genetic loci in its clinical phenotypes. The aim of this study was to determine the relationship between the MMP8 gene polymorphism and CRC risk in the Chinese Han population. METHOD: This study recruited 688 CRC patients and 690 healthy controls. The relationship between MMP8 polymorphism and CRC susceptibility was assessed by calculating the odds ratio (OR) and 95% confidence interval (CI) after stratifying by age, gender, body mass index (BMI), smoking, and alcohol consumption under a multi-genetic model. RESULTS: MMP8 rs3740938 was associated with increased CRC predisposition (p = 0.016, OR = 1.24, 95% CI: 1.04-1.48), and this association was detected particularly in subjects aged > 60 years, females, people with BMI > 24 kg/m2, smokers, and drinkers. Moreover, rs3740938 was found to be associated with the pathological type of rectal cancer. CONCLUSIONS: Our results first displayed that rs3740938 in MMP8 was a risk factor for CRC predisposition. This finding may provide a new biological perspective for understanding the role of the MMP8 gene in CRC pathogenesis.

The acetylation of pknH is linked to the ethambutol resistance of Mycobacterium tuberculosis.

EmbR, a substrate of pknH in Mycobacterium tuberculosis (Mtb), is related to the ethambutol (EMB) resistance. This study aimed to investigate the relationship between acetylation of pknH and the resistance of EMB mono-resistant Mtb. The EMB mono-resistant Mtb strain was constructed based on the MYCOTB and the Löwenstein-Jensen (LJ) proportion method. The growth kinetics was used to evaluate the bacterial growth. Escherichia coli, as the host of Mtb, was used for cloning and protein purification. Moreover, the immunoprecipitation was performed along with western blot to evaluate the EmbR phosphorylation and pknH acetylation. Each independent experiment was conducted in triplicate. EMB mono-resistant Mtb strain was successfully constructed according to the results of MIC values of 14 anti-Mtb drugs. The EMB resistant (ER) Mtb strain showed faster growth than the wild-type (WT) Mtb strain, and the difference was statistically significant. Moreover, pknH robustly phosphorylates EmbR, and pknH and acetylated pknH protein levels were downregulated in ER strain. The acetylation of pknH may reduce the phosphorylation of EmbR to inhibit the growth of Mtb strain. Enhancing the acetylation of pknH may be a promising method to inhibit the EMB resistance against Mtb.

Meta-Analysis of Functional Electrical Stimulation Combined with Occupational Therapy on Post-Stroke Limb Functional Recovery and Quality of Life.

OBJECTIVE: This study aimed to investigate whether Functional Electrical Stimulation (FES) and Transcranial Direct Current Stimulation (tDCS) enhanced the effect of Occupational Therapy (OT) on post-stroke limb functional recovery and quality of life, using direct and network meta-analysis. METHODS: A computerized search was conducted in databases such as Medline, Web of Science, Embase, CNKI (China National Knowledge Infrastructure), Wanfang Data, and VIP Information for prospective randomized controlled trials on OT, FES, and tDCS for improving post-stroke limb motor function and quality of life, with the search cutoff date of July 1, 2023. RESULTS: Following the screening process, a total of 8 research articles were incorporated, encompassing 358 participants. Among these, 177 individuals underwent OT exclusively, while 181 individuals underwent a combined regimen of OT alongside electromagnetic therapy. In terms of the intervention methods, the control group received OT treatment only, while the experimental group employed tDCS in 5 studies and FES in 3 studies. Within these investigations, Fugl-Meyer Assessment (FMA) scores were reported in 8 studies. The aggregated mean difference (MD) for FMA scores was 5.08 (95% CI: 2.46, 7.71), with a specific MD of 2.77 (95% CI: 1.46, 4.09) for the tDCS subgroup and 9.04 (95% CI: 5.34, 12.73) for the FES subgroup. Notably, FES combined with OT exhibited significant advantages in enhancing FMA scores when compared to the combination of tDCS and OT. Furthermore, four studies provided data on modified Barthel Index (MBI) scores, yielding a collective MD of 7.20 (95% CI: 4.44, 9.95). CONCLUSION: In patients with stroke, both FES combined with OT and tDCS combined with OT exhibit substantial enhancements in limb function and quality of life compared to OT alone. Notably, FES combined with OT yields superior clinical benefits when compared to the amalgamation of tDCS and OT.

The STING-IRF3 Signaling Pathway, Mediated by Endoplasmic Reticulum Stress, Contributes to Impaired Myocardial Autophagic Flux After Ischemia/Reperfusion.

ABSTRACT: This study aimed to determine whether endoplasmic reticulum (ER) stress is involved in impaired autophagy after myocardial ischemia/reperfusion (M-I/R) and elucidate the underlying mechanisms. The expression levels of stimulator of interferon gene (STING) and interferon regulatory transcription factor 3 (IRF3) phosphorylation increased in M-I/R heart tissues and hypoxia-treated/reoxygenation-treated H9c2 cells. The ER stress inhibitor 4-phenylbutyric acid (4-PBA) significantly suppressed the stimulation of STING-IRF3 transcription and alleviated cardiac dysfunction caused by M-I/R injury. In addition, 4-PBA reversed ischemia-induced/reperfusion-induced autophagic flux dysfunction, as demonstrated by a decrease in p 62 and LC3 levels. Similarly, the protective effect of STING deficiency on myocardial cell damage was achieved by the recovery of autophagic flux. Conversely, the protective effect of 4-PBA against hypoxia/reoxygenation injury in cardiomyocytes was offset by STING overexpression, wherein the activated STING-IRF3 pathway promoted the expression of Rubicon (a negatively-regulated autophagic molecule) by binding to the Rubicon promoter. Rubicon ablation effectively counteracts the adverse effects of STING overexpression in cardiomyocytes. The data showed that STING-IRF3 signaling of ER stress receptors is particularly important in the progression of physiological M-I/R caused by the inhibition of autophagic flow in vivo and in vitro.

Highly applicable dual-cathode electro-Fenton system with self-adjusting pH and ferrous species.

Due to the high dependence on the pH of influent water and the level of ferrous species, the applicability of the electro-Fenton (EF) system is poor. A highly applicable dual-cathode (DC) EF system with self-adjusting pH and ferrous species is proposed: gas diffusion electrode (GDE) for generation H2O2 and Fe/S doped multi-walled carbon nanotubes (Fe/S-MWCNT) modification active cathode (AC) for adjusting pH and iron species. The strong synergistic enhancement effect between two cathodes (synergy factor up to 90.3%) improves the catalytic activity of this composite system about 12.4 times higher than that of cathode alone. Impressively, AC has the ability of self-regulate to shift towards the optimal Fenton pH (around 3.0) without adding reagents. Even pH can be adjusted from 9.0 to 3.4 within 60 min. This characteristic gives the system a wide range of pH applications, while avoiding the disadvantage of the high cost of traditional EF in pre-acidification. Furthermore, DC has a high and stable ferrous species supply, and the iron leaching amount is about twice less than that of heterogeneous EF system. Long-term stability of the DC system and its easy activity regeneration exhibit the potential of environmental remediation in industrial application.

Investigating the electrochemical advanced oxidation mechanism of N-doped graphene aerogel: Molecular dynamics simulation combined with DFT method.

Nitrogen-doped graphene as a perfectly-efficient and environmentally compatible electrocatalyst won widespread attention in electrochemical advanced oxidation processes (EAOP). However, the relationship between surface structure regulation and activity of catalysts is still lacking in systematic scientific guidance. Herein, nitrogen-doped graphene aerogel (NGA) was conveniently prepared through hydrothermal treatment, and then utilized to fabricate the gas diffusion electrode (GDE) as the cathode for tetracycline (TC) removal. High free radical yield (81.2 µM) and fast reaction rate (0.1469 min-1) were found in NGA system. The molecular dynamics simulation (MD) results showed that the interaction energy of NGA was greater than the raw graphene aerogel (GA). The adsorption activation of H2O2 and the degradation of TC occurred in the first adsorption layer of catalysts, and both processes turned more orderly after nitrogen doping. Moreover, the van der Waals interaction was stronger than the electrostatic interaction. Density function theory (DFT) revealed that the adsorption energy of H2O2 at graphitic N, pyridinic N, and pyrrolic N sites was -0.03 eV, -0.39 eV, and -0.30 eV, respectively. Pyridinic N sites were inferred as the main functional regions of in-situ activation •OH, there were more likely to occur ectopic reaction in pyrrolic N, and graphitic N were responsible for improving H2O2 production. By revealing the microstructure and activation characteristics of NGA, an experiment-simulation complementary strategy is provided in the EAOP to discover or to optimize new catalysts.

The Value of Applying Machine Learning in Predicting the Time of Symptom Onset in Stroke Patients: Systematic Review and Meta-Analysis.

BACKGROUND: Machine learning is a potentially effective method for identifying and predicting the time of the onset of stroke. However, the value of applying machine learning in this field remains controversial and debatable. OBJECTIVE: We aimed to assess the value of applying machine learning in predicting the time of stroke onset. METHODS: PubMed, Web of Science, Embase, and Cochrane were comprehensively searched. The C index and sensitivity with 95% CI were used as effect sizes. The risk of bias was evaluated using PROBAST (Prediction Model Risk of Bias Assessment Tool), and meta-analysis was conducted using R (version 4.2.0; R Core Team). RESULTS: Thirteen eligible studies were included in the meta-analysis involving 55 machine learning models with 41 models in the training set and 14 in the validation set. The overall C index was 0.800 (95% CI 0.773-0.826) in the training set and 0.781 (95% CI 0.709-0.852) in the validation set. The sensitivity and specificity were 0.76 (95% CI 0.73-0.80) and 0.79 (95% CI 0.74-0.82) in the training set and 0.81 (95% CI 0.68-0.90) and 0.83 (95% CI 0.73-0.89) in the validation set, respectively. Subgroup analysis revealed that the accuracy of machine learning in predicting the time of stroke onset within 4.5 hours was optimal (training: 0.80, 95% CI 0.77-0.83; validation: 0.79, 95% CI 0.71-0.86). CONCLUSIONS: Machine learning has ideal performance in identifying the time of stroke onset. More reasonable image segmentation and texture extraction methods in radiomics should be used to promote the value of applying machine learning in diverse ethnic backgrounds. TRIAL REGISTRATION: PROSPERO CRD42022358898; https://www.crd.york.ac.uk/Prospero/display_record.php?RecordID=358898.

Post-Remedial Oxygen Supply: A New Perspective on Photodynamic Therapy to Suppress Tumor Metastasis.

Photodynamic therapy (PDT) holds great promise in tumor therapy due to high safety, efficacy, and specificity. However, the risk of increased metastasis in hypoxic tumors after oxygen-dependent PDT remains underestimated. Here, we propose a post-PDT oxygen supply (POS) strategy to reduce the risk of metastasis. Herein, biocompatible and tumor-targeting Ce6@BSA and PFC@BSA nanoparticles were constructed for PDT and POS in a 4T1-orthotropic breast cancer model. PDT with Ce6@BSA nanoparticles increased tumor metastasis via the HIF-1α signaling pathway, whereas POS significantly reduced the PDT-triggered metastasis by blocking this pathway. Furthermore, POS, with clinical protocols and an FDA-approved photosensitizer (hypericin), and oxygen inhalation reduced PDT-induced metastasis. Our study findings indicate that PDT may increase the risk of tumor metastasis and that POS may solve this problem. POS can reduce the metastasis resulting not only from PDT but also from other oxygen-dependent treatments such as radiotherapy and sonodynamic therapy.

Meconium-Stained Amniotic Fluid: Impact on Prognosis of Neonatal Bacterial Meningitis.

OBJECTIVES: Clinical data with respect to the impact of meconium on the prognosis of neonatal bacterial meningitis are scarce. Therefore, in this study, we aimed to determine whether meconium-stained amniotic fluid (MSAF) represents a risk factor for poor prognosis of neonatal bacterial meningitis in a confirmed case population. METHODS: This was a retrospective cohort study of 256 neonates diagnosed with bacterial meningitis hospitalized at one of three hospitals in Shantou, China, between October 2013 and September 2018. Clinical manifestation, laboratory test results and treatment were compared between the two groups, with outcomes dichotomized into 'good' or 'poor' prognosis. Multivariate analysis and follow-up logistic regression analysis were used to identify predictive factors of a poor outcome. RESULTS: Of the 256 neonates with BM, 95 (37.1%) had a good prognosis at discharge and 161 (62.9%) had a poor prognosis. In the poor prognosis group, 131/161 (79.4%) neonates had a permanent neurological sequelae and 19 (11.8%) had ≥2 sequelae. Of note, 11 neonates died. The rate of poor prognosis of BM was significantly higher among neonates with than without MSAF (26.1% vs. 12.6%, respectively; p < 0.05). A logistic multivariate analysis to evaluate the prognostic effect of MSAF to BM showed that neonatal with MSAF is more likely to have a worse prognosis of BM [unadjusted odds ratio (OR), 2.44, 95% confidence interval (CI), 1.24-5.10; adjusted OR, 2.31; 95% CI, 1.09-5.17]. CONCLUSION: MSAF is significantly associated with poor prognosis of neonatal bacterial meningitis. Therefore, in case of MSAF, more attention should be paid to neonatal bacterial meningitis.

Bioinspired Total Synthesis of (+)-Euphorikanin A.

We have achieved a bioinspired total synthesis of (+)-euphorikanin A, which possesses an intriguing and complex 5/6/7/3-fused tetracyclic skeleton bearing a bridged [3.2.1]-γ-lactone moiety. Key transformations include stereoselective alkylation and aldol condensation to install the main stereocenters, an intramolecular nucleophile-catalyzed aldol lactonization of carboxylic acid-ketone to assemble the five-membered ring, a McMurry coupling to construct the seven-membered ring, and a biomimetic benzilic acid type rearrangement to form the bridged [3.2.1]-γ-lactone moiety.

ZNF667 attenuates leukocyte-endothelial adhesion via downregulation of P-selectin in skin flap following remote limb ischemic preconditioning.

We assessed the effects and potential mechanism of romote ischemic preconditioning (RIPC) on leukocytes-endothelium cell adhesion in the flap microvessel after ischemia-reperfusion (I/R) injury. Eight hours after reperfusion, edema and intravascular leukocyte aggregation were reduced and microvessels were more obvious in the group with superficial inferior epigastric artery (SIEA) perforator flap (SIEA-flap) subjected to RIPC than in the I/R group. Zinc finger protein 667 (ZNF667) was significantly increased but P-selectin was decreased in the flaps subjected to RIPC, compared to those in the I/R group. The low expression of P-selectin was associated with ZNF667 expression and activation in human dermal microvascular endothelial cells in response to hypoxic preconditioning. ZNF667 bound to the P-selectin promoter region, suppressing its transcription through a special core sequence. The ablation of P-selectin by small interfering RNA effectively prevented the leukocytes-endothelium cell adhesion effect of ZNF667-knockdown. ZNF667 upregulation attenuates leukocyte-endothelial cell adhesion by negatively regulating the expression of P-selectin in SIEA-flap subjected to RIPC.

Railway Overhead Contact System Point Cloud Classification.

As the railway overhead contact system (OCS) is the key component along the high-speed railway, it is crucial to detect the quality of the OCS. Compared with conventional manual OCS detection, the vehicle-mounted Light Detection and Ranging (LiDAR) technology has advantages such as high efficiency and precision, which can solve the problems of OCS detection difficulty, low efficiency, and high risk. Aiming at the contact cables, return current cables, and catenary cables in the railway vehicle-mounted LiDAR OCS point cloud, this paper used a scale adaptive feature classification algorithm and the DBSCAN (density-based spatial clustering of applications with noise) algorithm considering OCS characteristics to classify the OCS point cloud. Finally, the return current cables, catenary cables, and contact cables in the OCS were accurately classified and extracted. To verify the accuracy of the method presented in this paper, we compared the experimental results of this article with the classification results of TerraSolid, and the classification results were evaluated in terms of four accuracy indicators. According to statistics, the average accuracy of using this method to extract two sets of OCS point clouds is 99.83% and 99.89%, respectively; the average precision is 100% and 99.97%, respectively; the average recall is 99.16% and 99.42%, respectively; and the average overall accuracy is 99.58% and 99.69% respectively, which is overall better than TerraSolid. The experimental results showed that this approach could accurately and quickly extract the complete OCS from the point cloud. It provides a new method for processing railway OCS point clouds and has high engineering application value in railway component detection.

[Analysis of prescription regularity of traditional Chinese medicine for colorectal cancer based on data mining].

The tumor prescriptions contained in Dictionary of Tumor Formulas, Compendium of Good Tumor Formulas, Chinese Pharmacopoeia, Ministry of Health Drug Standards for Chinese Medicine Formulas and National Compilation of Standards for Proprietary Chinese Medicines were selected and organized to construct a database for tumor prescriptions, and the data mining techniques were applied to investigate the prescription regularity of colorectal cancer prescriptions. The formula data were extracted after screening in strict accordance with the inclusion and exclusion criteria, and were then analyzed with Microsoft Excel 2010 for frequency statistics, Apriori block provided by SPSS Clementine 12.0 software for correlation rule analysis, and arules and arulesViz packages in R 4.0.2 software for correlation rule visualization. In addition, SPSS 18.0 software was used for cluster analysis and factor analysis, in which cluster analysis was performed by Ochiai algorithm with bicategorical variables in systematic clustering method and factor analysis was performed mainly with principal component analysis. A total of 285 prescriptions were included in the statistical analysis, and the frequency statistics showed that 43 herbs had been used more than 16 times. The association rules analysis showed that 26 high-frequency me-dicine pair rules were obtained, and the association rules for those dispelling evil spirits, strengthening the body, resolving stasis, dispelling dampness, etc. were visualized. In the cluster analysis, we generated a dendrogram from which 7 groups of traditional Chinese medicines with homogeneity were extracted. 10 common factors were obtained in the factor analysis. The types of herbal medicines involved in the colorectal cancer prescription included anti-cancer antidotes, strengthening and tonifying medicines, blood-regulating medicines, and expectorant medicines, corresponding to the treatment for eliminating evil spirits, strengthening, resolving stasis, and expectorating dampness. The prescriptions for anti-cancer detoxification were normally based on the pairs composed of Scutellaria barbata-Hedyotis diffusa and Sophora flavescens, Sargentodoxa cuneata, S. barbata, often combined with stasis relieving drug and dampness eliminating drug, reflecting the characteristics of treatment for both toxicity and stasis, dampness and toxicity simultaneously. The prescriptions for strengthening the righteousness and tonifying the deficiency were composed of Astragalus membranaceus and Atractylodes macrocephala mainly, exerting the effect of benefiting Qi, strengthening the spleen and drying dampness, tonifying kidney and essence, tonifying blood and invigorating blood. Meanwhile, anti-cancer detoxification medicines shall be reduced as much as possible. The compatibility of the medicines for the intestinal tract reflected the principle of using the right medicine for the right condition and eliminating evil spirits or strengthening the body, as appropriate.

Divergent Strategy in Natural Product Total Synthesis.

The divergent total syntheses of complex natural products from a common intermediate have attracted enormous attention in the chemical community in the past few years because it can improve the efficiency of chemical synthesis. A number of powerful and unified strategies have been developed by emulating the natural biosynthesis or through innovative transformations. This review focuses on the total synthesis of natural products by applying divergent strategies and the literature covering from 2013 to June 2017. On the basis of where the diversity comes from, the examples are grouped into three parts and discussed in detail. In each group, the examples that synthesize natural products belonging to the same subfamily are put together to contrast with one another.

Ultrafast spectroscopy of biliverdin dimethyl ester in solution: pathways of excited-state depopulation.

Biliverdin is a bile pigment that has a very low fluorescence quantum yield in solution, but serves as a chromophore in far-red fluorescent proteins being developed for bio-imaging. In this work, excited-state dynamics of biliverdin dimethyl ether (BVE) in solvents were investigated using femtosecond (fs) and picosecond (ps) time-resolved absorption and fluorescence spectroscopy. This study is the first fs timescale investigation of BVE in solvents, and therefore revealed numerous dynamics that were not resolved in previous, 200 ps time resolution measurements. Viscosity- and isotope-dependent experiments were performed to identify the contributions of isomerization and proton transfer to the excited-state dynamics. In aprotic solvents, a ∼2 ps non-radiative decay accounts for 95% of the excited-state population loss. In addition, a minor ∼30 ps emissive decay pathway is likely associated with an incomplete isomerization process around the C15[double bond, length as m-dash]C16 double bond that results in a flip of the D-ring. In protic solvents, the dynamics are more complex due to hydrogen bond interactions between solute and solvent. In this case, the ∼2 ps decay pathway is a minor channel (15%), whereas ∼70% of the excited-state population decays through an 800 fs emissive pathway. The ∼30 ps timescale associated with isomerization is also observed in protic solvents. The most significant difference in protic solvents is the presence of a >300 ps timescale in which BVE can decay through an emissive state, in parallel with excited-state proton transfer to the solvent. Interestingly, a small fraction of a luminous species, which we designate lumin-BVE (LBVE), is present in protic solvents.

Mesorhizobium alexandrii sp. nov., isolated from phycosphere microbiota of PSTs-producing marine dinoflagellate Alexandrium minutum amtk4.

An aerobic, Gram-stain-negative, motile and rod-shaped bacterial strain, designated as Z1-4T, was isolated from the phycosphere microbiota of marine dinoflagellate Alexandrium minutum that produces paralytic shellfish poisoning toxins. Phylogenetic analysis based on 16S rRNA gene sequences showed that the new isolate belongs to the genus Mesorhizobium, and it was closely related to Mesorhizobium waimense LMG 28228T and Mesorhizobium amorphae LMG 18977T with both 16S rRNA gene sequence similarities of 97.3%. The values of average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) relatedness between strain Z1-4T and its relatives are both well below the thresholds used for the delineation of a new species. A genome-based phylogenetic tree constructed by up-to-date bacterial core gene set (UBCG) indicates that strain Z1-4T forms an independent branch within the genus Mesorhizobium. The respiratory quinone of strain Z1-4T was Q-10. The major fatty acids were similar to other members of the genus Mesorhizobium containing the summed feature 8, C16:0, C19:0cycloω8c, C17:0 and summed feature 3. The polar lipids are phosphatidylmonomethylethanolamine, diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, an unidentified aminophospholipid, five glycolipids and seven unknown polar lipids. The DNA G + C content was determined to be 62.1 mol % based on its genomic sequence. Combined evidences based on the genotypic, chemotaxonomic and phenotypic characteristics clearly indicates that strain Z1-4T represents a novel species of the genus Mesorhizobium, for which the name Mesorhizobium alexandrii sp. nov. is proposed. The type strain is Z1-4T (= KCTC 72512T = CCTCC AB 2019101T).

Risk-adapted treatment reduced chemotherapy exposure for clinical stage I pediatric testicular cancer.

BACKGROUND: Different from adult clinical stage I (CS1) testicular cancer, surveillance has been recommended for CS1 pediatric testicular cancer. However, among high-risk children, more than 50% suffer a relapse and progression during surveillance, and adjuvant chemotherapy needs to be administered. Risk-adapted treatment might reduce chemotherapy exposure among these children. METHODS: A decision model was designed and calculated using TreeAge Pro 2011 software. Clinical utilities such as the relapse rates of different groups during surveillance or after chemotherapy were collected from the literature. A survey of urologists was conducted to evaluate the toxicity of first-line and second-line chemotherapy. Using the decision analysis model, chemotherapy exposure of the risk-adapted treatment and surveillance strategies were compared based on this series of clinical utilities. One-way and two-way tests were applied to check the feasibility. RESULTS: In the base case decision analysis of CS1 pediatric testicular cancer, risk-adapted treatment resulted in a lower exposure to chemotherapy than surveillance (average: 0.7965 cycles verse 1.3419 cycles). The sensitivity analysis demonstrated that when the relapse rate after primary chemotherapy was ≤ 0.10 and the relapse rate of the high-risk group was ≥ 0.40, risk-adapted treatment would result in a lower exposure to chemotherapy, without any association with the proportion of low-risk patients, the relapse rate of the low-risk group, the relapse rate after salvage chemotherapy or the toxicity utility of second-line chemotherapy compared to first-line chemotherapy. CONCLUSIONS: Based on the decision analysis, risk-adapted treatment might decrease chemotherapy exposure for these high-risk patients, and an evaluation after orchiectomy was critical to this process. Additional clinical studies are needed to validate this statement.