Phylogenetic trees have been extensively used in community ecology. However, how the phylogeny construction affects ecological inferences is poorly understood. In this study, we constructed three ...different types of phylogenetic trees (a synthetic‐tree generated using V.PhyloMaker, a barcode‐tree generated using rbcL+matK+trnH‐psbA, and a plastome‐tree generated from plastid genomes) that represented an increasing level of phylogenetic resolution among 580 woody plant species from six forest dynamic plots in subtropical evergreen broadleaved forests of China. We then evaluated the performance of each phylogeny in estimations of community phylogenetic structure, turnover and phylogenetic signal in functional traits. As expected, the plastome‐tree was most resolved and most supported for relationships among species. For local phylogenetic structure, the three trees showed consistent results with Faith's PD and MPD; however, only the synthetic‐tree produced significant clustering patterns using MNTD for some plots. For phylogenetic turnover, contrasting results between the molecular trees and the synthetic‐tree occurred only with nearest neighbor distance. The barcode‐tree agreed more with the plastome‐tree than the synthetic‐tree for both phylogenetic structure and turnover. For functional traits, both the barcode‐tree and plastome‐tree detected phylogenetic signal in maximum height, but only the plastome‐tree detected signal in leaf width. This is the first study that uses plastid genomes in large‐scale community phylogenetics. Our results highlight the improvement of plastome‐trees over barcode‐trees and synthetic‐trees for the analyses studied here. Our results also point to the possibility of type I and II errors in estimation of phylogenetic structure and turnover and detection of phylogenetic signal when using synthetic‐trees.
A novel palladium-catalysed ring-opening 3 + 2-annulation of spirovinylcyclopropyl oxindole with α,β-unsaturated nitroalkenes is reported. A series of spirooxindole derivatives were synthesized in ...high yields and good to excellent diastereoselectivities. This developed protocol offers a new and efficient pathway for the assembly of spirooxindoles.
Neutrophils are characterized by their heterogeneity. They fight against pathogens and are involved in tissue injury repair and immune system regulation. Neutrophils have an extremely short life span ...in the peripheral blood and undergo aging after being released from the bone marrow. The over-aggregation of aged neutrophils is associated with phenotypical and functional changes. Here, we aimed to investigate the dynamics of neutrophil aging and its relationship with T cell exhaustion in HIV-1 infection, as they are not well understood. In this study, we enrolled 23 treatment naïve (TN) patients, 23 individuals that had received antiretroviral therapy (ART), and 21 healthy controls (HC). In these cohorts, we measured the degree of neutrophil aging, and its possible correlation with T cell dysfunction. In TN patients, peripheral neutrophils showed a more distinct aging phenotype and were over-activated compared to those in ART-treated patients. The degree of neutrophil aging was positively correlated with HIV-1 RNA viral load and negatively correlated with CD4+ T cell count. Moreover, aged neutrophils had impaired reactive oxygen species (ROS) production after lipopolysaccharide (LPS) stimulation, and were characterized by increased PD-L1 and arginase-1 expression in a time-dependent manner. Aged neutrophils demonstrated an increased inhibition of IFN-γ and TNF-α secretion by CD8+ T cell compared to non-aged neutrophils. The inhibition effect could be partially reversed by blocking PD-L1 and arginase-1
in vitro
, and LPS was identified as an important activator of neutrophil aging. These results provide evidence that dampening neutrophil aging may provide a novel approach to recover T cell dysfunction in patients with HIV-1 infection.
To establish a clinically applicable genomic clustering system, we investigated the interactive landscape of driver mutations in intrahepatic cholangiocarcinoma (ICC).
The genomic data of 1481 ICCs ...from diverse populations was analyzed to investigate the pair-wise co-occurrences or mutual exclusivities among recurrent driver mutations. Clinicopathological features and outcomes were compared among different clusters. Gene expression and DNA methylation profiling datasets were analyzed to investigate the molecular distinctions among mutational clusters. ICC cell lines with different gene mutation backgrounds were used to evaluate the cluster specific biological behaviors and drug sensitivities.
Statistically significant mutation-pairs were identified across 21 combinations of genes. Seven most recurrent driver mutations (
,
,
,
/2,
and
) showed pair-wise co-occurrences or mutual exclusivities and could aggregate into three genetic clusters: Cluster1: represented by tripartite interaction of
,
and
mutations, exhibited large bile duct histological phenotype with high CA19-9 level and dismal prognosis; Cluster2: co-association of
/
or
/
mutation, was characterized by small bile duct phenotype, low CA19-9 level and optimal prognosis; Cluster3: mutation-free ICC cases with intermediate clinicopathological features. These clusters showed distinct molecular traits, biological behaviors and responses to therapeutic drugs. Finally, we identified S100P and KRT17 as "cluster-specific", "lineage-dictating" and "prognosis-related" biomarkers, which in combination with CA19-9 could well stratify Cluster3 ICCs into two biologically and clinically distinct subtypes.
This clinically applicable clustering system can be instructive to ICC prognostic stratification, molecular classification, and therapeutic optimization.
Abstract Invasive brain glioma is the most lethal type of cancer and is highly infiltrating. This leads to an extremely poor prognosis and makes complete surgical removal of the tumor virtually ...impossible. Non-penetration of therapeutic drugs across the blood–brain barrier (BBB), brain cancer stem cells (CSCs), and brain cancer vasculogenic mimicry (VM) results in relapse after surgical and radio therapy. We developed a functional targeting chemotherapy for transporting drugs across the BBB, destroying VM channels, and eliminating CSCs and cancer cells in the brain. The studies were undertaken on brain glioma cells in vitro and in brain glioma-bearing rats. Using paclitaxel as the anticancer drug and artemether as the regulator of apoptosis and inhibitor of VM channels, a kind of functional targeting paclitaxel plus artemether liposomes was developed by modifying two new functional materials: a mannose-vitamin E derivative conjugate (MAN-TPGS1000 ) and a dequalinium-lipid derivative conjugate (DQA-PEG2000 -DSPE). The transport mechanism across the BBB was associated with receptor-mediated endocytosis by MAN-TPGS1000 conjugate via glucose transporters and adsorptive-mediated endocytosis by DQA-PEG2000 -DSPE conjugate via electric charge-based interactions. The efficacy was related to the destruction of VM channels by regulating VM indicators, as well as the induction of apoptosis in brain cancer cells and CSCs by activating apoptotic enzymes and pro-apoptotic proteins and inhibiting anti-apoptotic proteins. These data suggest that the chemotherapy using functional targeting paclitaxel plus artemether liposomes could provide a new strategy for treating invasive brain glioma.
Continuous 6‐mercaptopurine (6‐MP) dose titration is necessary because of its narrow therapeutic index and frequently encountered dose‐limiting hematopoietic toxicity. However, evidence‐based ...guidelines for gene‐based 6‐MP dosing have not been established for Chinese children with acute lymphoblastic leukemia (ALL). This multicenter, randomized, open‐label, active‐controlled clinical trial randomly assigned Chinese children with low‐ or intermediate‐risk ALL in a 1:1 ratio to receive TPMT–NUDT15 gene–based dosing of 6‐MP (N = 44, 10 to 50 mg/m2/day) or standard dosing (N = 44, 50 mg/m2/day) during maintenance therapy. The primary end point was the incidence of 6‐MP myelosuppression in both groups. Secondary end points included frequencies of 6‐MP hepatotoxicity, duration of myelosuppression and leukopenia, event‐free survival, and steady‐state concentrations of active metabolites (6‐thioguaninenucleotides and 6‐methylmercaptopurine nucleotides) in erythrocytes. A 2.2‐fold decrease in myelosuppression, the primary end point, was observed in the gene‐based–dose group using ~ 50% of the standard initial 6‐MP dose (odds ratio, 0.26, 95% confidence interval, 0.11 to 0.64, P = 0.003). Patients in the gene‐based–dose group had a significantly lower risk of developing thiopurine‐induced myelosuppression and leukopenia (P = 0.015 and P = 0.022, respectively). No significant differences were observed in the secondary end points of the incidence of hepatotoxicity and steady‐state concentrations of active metabolites in erythrocytes between the two groups. TPMT‐ and NUDT15‐based dosing of 6‐MP will significantly contribute toward further reducing the incidence of leukopenia in Chinese children with ALL. This trial is registered at www.clinicaltrial.gov as #NCT04228393.
Dose reduction is strongly recommended for patients with loss‐of‐function TPMT and NUDT15 alleles to reduce the risk of thiopurine‐related toxicity.
Background
Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous disease with major diagnostic and therapeutic difficulties. A large‐scale multicenter study of pediatric HLH is still lacking in ...China.
Procedure
The Histiocytosis Study Group of the Chinese Pediatric Society conducted this retrospective study in 2014. A total of 323 patients diagnosed with HLH between 2011 and 2013 from 12 hospitals were registered.
Results
The median age at diagnosis was 2.2 years (range, 0–14.6 years), with a peak age of HLH onset at 0 to 3 years (63%). Mutations in HLH‐related genes were found in 27.9% (24/86) patients who underwent genetic testing. PRF1, UNC13D, STXBP2 and LYST were the predominant genes involved. Sixteen patients (66.7%) presented with only monoallelic mutations in one gene. Epstein‐Barr virus (EBV) infection was the major condition related to HLH, which was documented in 74.4% (201/270) of the patients who underwent EBV detection. Of 252 evaluable patients, 64.7% (163) achieved non‐active disease at the eighth week and patients treated with a protocol containing etoposide presented higher remission rates (75.6% vs. 46.8%, P < 0.001). In multivariate analysis, a younger age at diagnosis (<12 months), platelet count less than 80×109/L, central nervous system involvement, and initial treatment using a protocol without etoposide (not HLH‐94/04) were independent prognostic factors indicating resistant disease.
Discussion
This study first multicenter assessment of HLH in China shows some different features in Chinese children with HLH compared with those in western countries, including older age, vulnerability to EBV infection, and a high proportion of patients with single monoallelic genetic mutations.
Vascular peroxidase 1 (VPO1) plays an important role in mediation of vascular remodeling with pulmonary arterial hypertension (PAH). This study aims to determine whether VPO1 can promote phenotypic ...transformation of pulmonary artery smooth muscle cells (PASMCs) and the underlying mechanisms.
Sprague-Dawley (SD) rats were exposed to 10 % O2 for 21 days to establish the model of vascular remodeling in pulmonary arterial hypertension. PASMCs were incubated with 3 % O2 for 48 h to induce phenotypic transformation. Western blot was performed to detect the expressions of target proteins. The 5-ethynyl-2′-deoxyuridine (EdU) assay was conducted to measure the proliferation of PASMCs.
In the rats exposed to hypoxia, there were increases in right ventricular systolic pressure, pulmonary vascular remodeling and phenotypic transformation of PASMCs (the down-regulated contractile proteins of α-smooth muscle actin, smooth muscle 22α while the up-regulated synthetic proteins of osteopontin, cyclinD1), accompanied by up-regulation of VPO1, increase of hypochlorous acid (HOCl) production and elevation of the phosphorylation of ERK. In the cultured PASMCs exposed to hypoxia, similar results were achieved but they were reversed by VPO1 small interfering RNA (VPO1 siRNA) or HOCl inhibitor. Replacement of hypoxia with NaOCl could induce PASMCs phenotypic transformation and activate the ERK signaling. Furthermore, ERK inhibitor (PD98059) could also attenuate hypoxia-induced PASMCs phenotypic transformation.
VPO1 play a pivotal role in promotion of phenotypic transformation of PASMCs under hypoxic condition through activation of VPO1/HOCl/ERK pathway. It might serve as a potential target for prevention of pulmonary vascular remodeling.
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Accumulating evidence shows that circular RNAs (circRNAs) plays vital roles in tumor progression. However, the biological functions of circRNAs in laryngeal squamous cell carcinoma (LSCC) metastasis ...is still unclear.
qRT-PCR was used to detect circFLNA, miRNAs and FLNA mRNA expression. Transwell assay and western blot were performed to evaluate cell migration ability and to detect FLNA, MMP2 and MLK1 protein expression, respectively. RNA pull-down analysis was used to find the binding-miRNAs of circFLNA. Luciferase reporter assay was used to examine the effect of circFLNA on miRNAs and miR-486-3p on FLNA expression.
In this study, we confirmed that a Filamin A (FLNA)-derived hsa_circ_0092012 known as circFLNA, was upregulated in LSCC, and the higher expression of circFLNA was correlated with LSCC lymph node metastasis. Increased circFLNA facilitates LSCC cell migration ability through upregulating FLNA and MMP2 protein expression. Mechanistically, we find that circFLNA sponges miR-486-3p in LSCC cells, relieving miR-486-3p-induced repression of FLNA which promotes LSCC cell migration. Accordingly, FLNA mRNA is overexpressed in LSCC tissues and a higher FLNA level is correlated with poor survival. Dysregulation of the circFLNA/miR-486-3p/FLNA regulatory pathway contributes to LSCC migration.
In summary, our study sheds light on the regulatory mechanism of circFLNA in LSCC migration via sponging miR-486-3p, which downregulates the FLNA protein expression. Targeting circFLNA/miR-486-3p/FLAN axis provides a potential therapeutic target for aggressive LSCC.
The sluggish kinetics of the ethanol oxidation reaction (EOR) challenges us to design and synthesize high-performance multicomponent nanocatalysts. Here, we report the intrinsic composition and ...electronic effects for achieving enhanced catalytic performance in the EOR by a combination of experiments and density functional theory (DFT) computations. Late 3d transition metals and main group (IIIA and IVA) metals were introduced to construct ternary Pt
3
RhM (M = Fe, Co, Ni, Cu; Ga, In, Sn, Pb) nanoalloys with similar geometric structures (nearly spherical) and crystallite sizes (
ca.
8.5 nm) by a one-pot solvothermal method. The main group metals outperformed the transition metals in the enhancement of EOR activity and CO
2
selectivity. In particular, Pt
3
RhSn/C exhibited 67- and 7-fold increases in specific activity and mass activity, respectively, at 0.45 V (
vs.
RHE) in the EOR in acidic conditions in comparison with a commercial Pt/C catalyst. The trends in catalytic activity were explained by DFT calculations, which established a volcano-shaped relationship between the EOR activity and the sum of the binding energies of oxygen and carbon (
E
O
+
E
C
). Among the above catalysts, the state-of-the-art Pt
3
RhSn/C catalyst performed best in terms of an optimum value of
E
O
+
E
C
with a moderate adsorption strength of stable intermediates. In addition, the CO
2
selectivity was linearly correlated with the sum of the binding energies of oxygen and H
2
O (
E
O
+
E
H2O
), which closely matched the experimental results for typical catalysts. Therefore, the values of
E
O
+
E
C
and
E
O
+
E
H2O
served as descriptors of activity and selectivity, respectively, to rationalize and predict the chemical trends observed in experiments on the EOR catalyzed by nanoalloys. The concept that was revealed, namely, that the composition–performance relationship originates from the synergistic electronic effects of the nanoalloys, promises an alternative strategy for the development of novel solid catalysts for the EOR.
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