Overexpression of malic enzyme is involved in breast cancer growth and is correlated with poor prognosis.

Malic enzyme (ME) genes are key functional metabolic enzymes playing a crucial role in carcinogenesis. However, the detailed effects of ME gene expression on breast cancer progression remain unclear. Here, our results revealed ME1 expression was significantly upregulated in breast cancer, especially in patients with oestrogen receptor/progesterone receptor-negative and human epidermal growth factor receptor 2-positive breast cancer. Furthermore, upregulation of ME1 was significantly associated with more advanced pathological stages (p < 0.001), pT stage (p < 0.001) and tumour grade (p < 0.001). Kaplan-Meier analysis revealed ME1 upregulation was associated with poor disease-specific survival (DSS: p = 0.002) and disease-free survival (DFS: p = 0.003). Multivariate Cox regression analysis revealed ME1 upregulation was significantly correlated with poor DSS (adjusted hazard ratio [AHR] = 1.65; 95% CI: 1.08-2.52; p = 0.021) and DFS (AHR, 1.57; 95% CI: 1.03-2.41; p = 0.038). Stratification analysis indicated ME1 upregulation was significantly associated with poor DSS (p = 0.039) and DFS (p = 0.038) in patients with non-triple-negative breast cancer (TNBC). However, ME1 expression did not affect the DSS of patients with TNBC. Biological function analysis revealed ME1 knockdown could significantly suppress the growth of breast cancer cells and influence its migration ability. Furthermore, the infiltration of immune cells was significantly reduced when they were co-cultured with breast cancer cells with ME1 knockdown. In summary, ME1 plays an oncogenic role in the growth of breast cancer; it may serve as a potential biomarker of progression and constitute a therapeutic target in patients with breast cancer.

Population pharmacokinetics of mirvetuximab soravtansine in patients with folate receptor-α positive ovarian cancer: The antibody-drug conjugate, payload and metabolite.

AIMS: Mirvetuximab soravtansine is a first-in-class antibody-drug conjugate recently approved for the treatment of folate receptor-α positive ovarian cancer. The aim of this study was to develop a population pharmacokinetic model to describe the concentration-time profiles of mirvetuximab soravtansine, the payload (DM4) and a metabolite (S-methyl-DM4). METHODS: Mirvetuximab soravtansine was administered intravenously from 0.15 to 7 mg/kg to 543 patients with predominantly platinum-resistant ovarian cancer in 3 clinical studies, and the plasma drug concentrations were analysed using a nonlinear mixed-effects modelling approach. Stepwise covariate modelling was performed to identify covariates. RESULTS: We developed a semi-mechanistic population pharmacokinetic model that included linear and nonlinear routes for the elimination of mirvetuximab soravtansine and a target compartment for the formation and disposition of the payload and metabolite in tumour cells. The clearance and volume of the central compartment were 0.0153 L/h and 2.63 L for mirvetuximab soravtansine, 8.83 L/h and 3.67 L for DM4, and 2.04 L/h and 6.3 L for S-methyl-DM4, respectively. Body weight, serum albumin and age were identified as statistically significant covariates. Exposures in patients with renal or hepatic impairment and who used concomitant cytochrome P450 (CYP) 3A4 inhibitors were estimated. CONCLUSION: There is no need for dose adjustment due to covariate effects for mirvetuximab soravtansine administered at the recommended dose of 6 mg/kg based on adjusted ideal body weight. Dose adjustment is not required for patients with mild or moderate renal impairment, mild hepatic impairment, or when concomitant weak and moderate CYP3A4 inhibitors are used.

Exposure-response relationships of mirvetuximab soravtansine in patients with folate receptor-α-positive ovarian cancer: Justification of therapeutic dose regimen.

AIMS: This study aimed to investigate exposure-response (ER) relationships in efficacy and safety for mirvetuximab soravtansine (MIRV) which is a first-in-class antibody-drug conjugate approved for the treatment of folate receptor-α-positive platinum-resistant ovarian cancer. METHODS: MIRV was characterized in 4 clinical studies. Exposure metrics for MIRV, its payload and a metabolite were derived from a population pharmacokinetic model. Efficacy was analysed in MIRV-treated patients (n = 215) in a recent confirmatory, randomized, chemotherapy-controlled MIRASOL trial and safety was evaluated in patients pooled across all 4 clinical studies (n = 757). RESULTS: In the MIRASOL trial (NCT04209855), MIRV demonstrated significant benefit over chemotherapy in progression-free survival (PFS), objective response rate (ORR) and overall survival (OS). The most common adverse events (AEs) included ocular disorders, peripheral neuropathy and pneumonitis. For PFS, ORR and OS, the trough concentration of MIRV was the predictor consistently found in ER models for efficacy. In contrast, for ocular AEs (as well as the time to onset of ocular AEs) and peripheral neuropathy, the area under the concentration-time curve (AUC) of MIRV was identified as the exposure metric in ER models for safety. No exposure parameters were found to correlate with pneumonitis. Covariates in all models did not show clinically meaningful impact on efficacy or safety. Logistic regression models for ORR and ocular AEs based on AUC of MIRV were used to justify the clinical dose regimen approved for MIRV. CONCLUSION: The trough concentration of MIRV correlated with efficacy whereas the AUC of MIRV was associated with major AEs. The ER relationships supported the selected therapeutic dose regimen.

Predicted changes in distribution and grazing value of Stipa-based plant communities across the Eurasian steppe.

The Eurasian steppe is one of the world's largest continuous areas of grassland and has an important role in supporting livestock grazing, the most ubiquitous land use on Earth. However, the Eurasian steppe is under threat, from irrational grazing utilization, climate change, and resource exploitation. We used an ensemble modeling approach to predict the current and future distribution of Stipa-dominated plant communities in three important steppe subregions; the Tibetan Alpine, Central Asian, and Black Sea-Kazakhstan subregions. We combined this with an assessment of the grazing value of 22 Stipa species, the dominant grassland species in the area, to predict how grazing value might change under future climate change predictions. We found that the effects of changing climates on grazing values differed across the three subregions. Grazing values increased in the Tibetan alpine steppe and to a lesser extent in Central Asia, but there were few changes in the Black Sea-Kazakhstan subregion. The response of different species to changing climates varied with environmental variables. Finally, our trait-based assessment of Stipa species revealed variations in grazing value, and this had major effects on the overall grazing value of the region. Our results reinforce the importance of trait-based characteristics of steppe plant species, how these traits affect grazing value, and how grazing values will change across different areas of the Eurasian steppe. Our work provides valuable insights into how different species will respond to changing climates and grazing, with important implications for sustainable management of different areas of the vast Eurasian steppe ecosystem.

A digital technique for occlusal design of a posterior full crown based on physiological tooth displacement and occlusion of adjacent teeth.

This article presents a digital technique to construct a virtual occlusion in the maximal intercuspal position (MIP), considering physiological tooth displacement and reducing intermesh penetrations between occlusal surfaces, in order to design more precise and accurate occlusal contacts of a posterior full crown.

[Intestinal absorption components and absorption characteristics of Wuwei Qingzhuo San by everted intestinal sac models].

This study investigated the absorption profile of Wuwei Qingzhuo San in different intestinal segments and the absorption characteristics of its alkaloids(piperine, piperanine, piperlonguminine, and dihydropiperlonguminine). The everted gut sac model was established, and the chemical components of Wuwei Qingzhuo San in different intestinal segments were detected by UPLC-Q-TOF-MS. The content of piperine, piperanine, piperlonguminine, and dihydropiperlonguminine in intestinal absorption fluid was determined by UPLC-Q-TRAP-MS and the absorption parameters were calculated. The absorption characteristics in different intestinal segments at different time were analyzed. As a result, 27, 27, 8, and 6 absorbent components from Wuwei Qingzhuo San were detected in the intestinal cyst fluid of jejunum, ileum, duodenum, and colon by UPLC-Q-TOF-MS technology, respectively. It was also found that piperine, piperanine, piperlonguminine, and dihydropiperlonguminine from Wuwei Qingzhuo San showed linear absorption in various intestinal segments, with r values exceeding 0.9. In terms of absorption content, the components were ranked as piperine>piperanine>dihydropiperlonguminine>piperlonguminine in various intestinal segments, but the absorption rate and mechanism of each component varied. The results demonstrate that the absorption of the components of Wuwei Qingzhuo San in different intestinal segments is selective and is not a simple semi-permeable membrane permeation process.

Effect of a novel interocclusal recording method on occlusal accuracy of implant-supported fixed prostheses: A randomized clinical trial.

OBJECTIVES: To investigate the effect of a novel interocclusal recording method on the occlusal accuracy of implant-supported fixed prostheses for partially dentate patients with distal extension. MATERIALS AND METHODS: Twenty patients with two or more adjacent teeth missing in the distal extension and scheduled to receive implant-supported fixed prostheses were enrolled. Two interocclusal recording methods were used: placing polyvinyl siloxane (PVS) on the interocclusal recording caps (test), and placing PVS on healing abutments (control). The intraoral occlusal contacts in maximal intercuspal position (MIP) were compared with those in the mounted casts to calculate sensitivity and positive predictive value (PPV). Then, patients were randomly allocated into two groups to determine which interocclusal record would be used. The implant prostheses' evaluations mainly included occlusal adjustment height, volume, and time, occlusal contact score based on articulating paper examination. Paired-samples t-test, Mann-Whitney U test, and least squares regression analyzed the statistic differences. RESULTS: The test method had higher sensitivity to detect intraoral occlusal contacts than the control method (p = .002), but similar PPV (p = .10). During the prostheses' evaluations, the occlusal adjustment height in the test group was significantly lower than that in the control group [99.4 (53.2, 134.2) vs. 159.0 (82.3, 247.8) µm, p = .03], while the occlusal contact score before adjustment was higher (p = .006). The groups had similar occlusal adjustment volume and time. CONCLUSIONS: The novel interocclusal recording method for implant-supported fixed prostheses was more accurate and could reduce the occlusal adjustment.

The effect of secukinumab treatment for psoriasis on serum cytokines and correlation with disease severity.

OBJECTIVE: To investigate the effects of secukinumab treatment for psoriasis on different functional cytokines and inflammatory mediators in patients' serum METHODS: Enzyme-linked immunosorbent assay was used to detect interleukin (IL)-1ß and IL-1RA associated with intrinsic immunity; IL-6, IL-18, and growth regulated oncogene alpha (GROα) associated with neutrophils; IL-12, tumour necrosis factor (TNF)-α, and interferon (IFN)-γ associated with Th1; IL-23, IL-17A, and IL-22 associated with Th17; Thymus activation regulated chemokine (TARC), IL-13, and defensin beta 2 (DEFB2) associated with Th2; Vascular endothelial growth factor (VEGF)-A and IL-10 associated with angiogenesis; and IFN-γ associated with sepsis in the peripheral blood of 12 patients with common psoriasis treated with secukinumab and 15 healthy controls. IL-23, IL-17A, IL-22 associated with Th17; TARC, IL-13, DEFB2 associated with Th2; VEGF-A, IL-10 associated with angiogenesis and procalcitonin (PCT) associated with sepsis. The differences in expression of the above cytokines before and after treatment and the correlation with psoriasis disease severityï¼»Psoriasis Area Severity Index(PASI) scoreï¼½, age, and disease duration were analyzed. RESULTS: The mean PASI score of the enrolled patients with moderate to severe psoriasis was 21.6 ± 11.0 before treatment and decreased to below 1 after treatment. Serum IL-6; IL-18, GROα, IFN-γ, TNF-α, VEGF-A, and IL-17A were significantly higher than normal. And IL-17A and IFN-γ were positively correlated with disease duration and age, and IL-18 was positively correlated with PASI score. The expression levels of IL-6, GROα, VEGF-A, IFN-γ, TNF-α, IL-17A and IL-23 were significantly lower after secukinumab treatment compared with those before treatment, but the expression levels of IFN-γ, VEGF-A, TARC, IL-13, and DEFB2 were still significantly higher than those of normal subjects after treatment CONCLUSIONS: secukinumab clears skin lesions by antagonizing IL-17A and simultaneously decreasing the expression levels of IL-6, GRO α, VEGF-A, IFN-γ, TNF-α, IL-17A, and IL-23.

Digitally designed occlusion of an implant-supported crown considering physiological tooth displacement under occlusal loading.

Physiological natural tooth displacement under occlusal loading can influence intraoral occlusal contacts. However, gypsum casts and digital scans cannot simulate the physiological tooth displacement under occlusal loading. The occlusal design of the implant-supported crowns has been based mainly on the experience of dental laboratory technicians, lacking accuracy and individualization. Therefore, a digital technique that considers physiological tooth displacement is presented to design the occlusion of implant-supported single crowns.

Assessment of physiological posterior-tooth displacement under habitual occlusal force by intraoral scanning using implant-supported crowns as the reference.

STATEMENT OF PROBLEM: Studies that have used digital methods to quantitatively evaluate physiological tooth displacement under occlusal force are sparse. PURPOSE: The purpose of this clinical study was to measure physiological posterior tooth displacement under occlusal force by intraoral scanning and reverse engineering technology by using implants as the reference. MATERIAL AND METHODS: A total of 14 participants received 15 implant-supported single mandibular first molar crowns. The surface data of maxillary and mandibular posterior teeth (U1 and L1) and the buccal occlusal data in the maximum intercuspal position (MIP) with habitual occlusal force were obtained by using an intraoral scanner (TRIOS 3, v20.1.2). The U1 and L1 data were segmented into single teeth, which were then aligned to the buccal occlusal data by using the "best-fit alignment" command to build the data under occlusal force (U2 and L2). U1 and L1 data were compared with U2 and L2 data to calculate the centroid and functional cusp vertex displacements and the long axis deflections of the second premolars and second molars, taking the first molar as the reference. The medians, and first quartile (Q1), third quartile (Q3) of the above data were reported, and the Shapiro-Wilk and Wilcoxon tests were used to analyze the differences (α=.05). RESULTS: Under occlusal force, the median (Q1, Q3) centroid displacements of posterior teeth ranged from 61 (52, 101) µm to 146 (80, 186) µm; the functional cusp vertex displacements ranged from 82 (62, 117) µm to 146 (98, 189) µm, and the long axis deflections ranged from 0.45 (0.25, 0.87) degrees to 1.03 (0.52, 1.41) degrees. Mandibular second premolars displaced lingually, mesially, and apically; mandibular second molars displaced distally and apically; and maxillary second premolars and second molars displaced lingually and apically. CONCLUSIONS: A digital method taking implant-supported single crowns as the reference was used to demonstrate physiological posterior-tooth displacement under habitual occlusal force.

TARS2 variants causes combination oxidative phosphorylation deficiency-21: a case report and literature review.

OBJECTIVE: To explore the clinical characteristics and genetic characteristics of the combined oxidative phosphorylation defect type 21 (COXPD21) caused by the TARS2 compound heterozygous varians, and to improve clinicians' awareness of the disease. METHODS: The clinical performance, diagnosis and treatment process and gene characteristics of COXPD21 caused by TARS2 were reviewed and analyzed and reviewed combined with the literature. RESULTS: The proband was a girl, the first birth, with repeated refractory hypokalemia, hearing impairment, developmental delay and intellectual disability，development backwardness after infection, high limb muscle tension, and increased serum lactate as the clinical phenotype. Two heterozygous varians in the TARS2 gene were detected by whole exome sequencing, one of which was c.1679(exon14) A > C (p.Asp560Ala) missense , which was derived from the mother, and the other was c.1036(exon10)C >T (p.Arg346Cys) missense variant, derived from the father, the child was diagnosed with COXPD21. The literature collected from the CNKI, Wanfang data and biomedical literature database (PubMed) until November 2021 were searched and reviewed with the key words "mitochondrial encephalomyopathy", "TARS2" and "combined oxidative phosphorylation deficiency type 21". A total of four complete domestic and foreign cases were collected from the literature search. CONCLUSION: COXPD21 onset by complex heterozygous variant of TARS2 causes refractory hypokalemia, which is rarely reported at home and abroad.

The effects of genital myiasis on the diversity of the vaginal microbiota in female Bactrian camels.

BACKGROUND: Genital myasis is one of the most important diseases that affects the reproductive organs of Bactrian camels in which can cause serious mechanical damage to the vaginal tissue. The accumulation of bacteria in the vagina of female camels can affect their health and reproductive ability. The effect of this damage is commonly manifested in the vaginal flora and vaginal mucosal immune system. Therefore, this investigation is a study of the diversity of the vaginal flora and the differences between healthy Bactrian camels and those suffering from genital myiasis. RESULTS: Vaginal microbiota samples were collected from two groups of female Bactrian camels of the same age. An Illumina MiSeq was used to sequence the 16S rRNA V3-V4 hypervariable sequence in the samples. The results showed that the vaginal microflora of the infected camels had a significantly greater operational taxonomic unit (OTU) value. According to the assessment of the alpha diversity index and the vaginal pH, the diversity index of the infected camel flora was higher than that of the normal camel flora, and the vaginal pH was lower than that of the normal camels (p < 0.01). There were no significant differences between the two groups in the abundance of dominant genera in the Bactrian camel vagina (P > 0.05), indicating that the certain stability is maintained. CONCLUSIONS: Overall, this comparison revealed the differences and similarities between the vaginal microbiota of Bactrian camels in various health statues. In addition, these data provide a reference point for understanding the types of bacteria that cause genital myiasis affecting the healthy development of Bactrian camels.

Molecular mechanism of benzo [a] pyrene regulating lipid metabolism via aryl hydrocarbon receptor.

BACKGROUND: Benzo [a] pyrene (BaP), a potent carcinogen, has been proved that it has toxicological effects via activation the aryl hydrocarbon receptor (AhR) pathway. AhR can participate in regulating lipogenesis and lipolysis. This topic will verify whether BaP regulates lipid metabolism via AhR. METHODS: (1) C57BL/6 mice were gavaged with BaP for 12 weeks to detect serum lipids, glucose tolerance, and insulin resistance. Morphological changes in white adipose tissue (WAT) were detected by Hematoxylin and Eosin staining. The mRNA expression levels of adipogenesis-related factors included recombinant human CCAAT/enhancer binding protein alpha (C/EBPα), peroxisome proliferator-activated receptor gamma (PPARγ), and fatty acid binding protein 4 (FABP4) and inflammatory factors included nuclear factor kappa-B (NF-κB), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α) were detected using PCR. (2) Neutral lipid content changes in differentiated 3 T3-L1 adipocytes treated with BaP with and w/o AhR inhibitor were detected by Oil red staining. The protein expression levels of adipogenesis- and decomposition-related factors included PPARγ coactivator-1 alpha (PGC-1α), and peroxisome proliferation-activated receptor alpha (PPARα) were detected using western blotting. The mRNA expression levels of inflammatory factors were detected using PCR. RESULTS: (1) BaP inhibited body weight gain, decreased lipid content, increased lipid levels, and decreased glucose tolerance and insulin tolerance in mice; (2) BaP reduced the expressions of C/EBPα, PPARγ, FABP4, PGC-1α, and PPARα and increased the expressions of NF-κB, MCP-1, and TNF-α by activating AhR. CONCLUSION: BaP inhibit fat synthesis and oxidation while inducing inflammation by activating AhR, leading to WAT dysfunction and causing metabolic complications.

Dictamnine inhibits pancreatic cancer cell growth and epithelial-mesenchymal transition by blocking the PI3K/AKT signaling pathway.

Many different treatments are available for pancreatic cancer (PC), including surgical resection, chemotherapy, radiotherapy, and immunotherapy, but these treatments are often ineffective at curing PC. Hence, identifying new and effective agents or strategies to improve therapeutic effects is critical. This study focused on the efficacy of dictamnine (DTM), a furan quinoline alkaloid extracted from Dictamnus dasycarpus Turcz., in treating PC. Our in vitro results showed that DTM can mitigate cell proliferation and induce cell cycle arrest and apoptosis in two different human PC cell lines. Moreover, epithelial-mesenchymal transition (EMT) was prevented during DTM treatment, reflected by reduced cell migration and invasion abilities. In vivo studies demonstrated that DTM treatment led to a remarkable inhibition of tumor growth in a xenograft nude mouse model. Mechanistic investigation showed that DTM might act by restraining constitutive and induced PI3K/AKT activity. In summary, our results demonstrated that DTM slows PC progression by inhibiting the activity of the PI3K/AKT signaling pathway and its downstream effectors and that DTM is effective as a pathway-specific cancer therapy. These findings could provide a greater understanding of the function of anticancer drugs and new options for PC treatment.

Characterization of the complete mitochondrial genome of the fluke of turdus, Plagiorchis elegans, and phylogenetic implications.

Plagiorchis elegans (Trematoda: Digenea) is mainly parasitic in the intestines of vertebrate animals, including humans, causing irreversible pathological damage and herd-spherical influences. However, little information is available about its molecular epidemiology, population genetics, and phylogeny. In the present study, we sequenced, assembled, and annotated the complete mitochondrial (mt) genome of P. elegans. Combining with the available mitochondrial data of subclass Digenea, phylogenetic analysis was performed based on Bayesian inference (BI). These results showed that the complete length of P. elegans is 13,862 bp, including 12 protein-coding genes (PCGs), 2 ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), and one non-coding region (NCR). There was an obvious A + T content from 61.0% to 71.3% and the values of the Ka/Ks ratio ranged from 0.119 (cox1) to 1.053 (nad6). In the BI analysis, different from previous studies, phylogenetic analysis showed genus Glypthelmins was paraphyletic rather than monophyletic and had a closer relationship with Plagiorchis and Orientocreadium. Additionally, the BI tree also presented that the genus Echinostoma was monophyletic. Our results provided molecular data in the family Plagiorchiidae proposing new insight within Xiphidiata and Echinostomata.

Breast Cancer with Increased Drug Resistance, Invasion Ability, and Cancer Stem Cell Properties through Metabolism Reprogramming.

Breast cancer is a heterogeneous disease, and the survival rate of patients with breast cancer strongly depends on their stage and clinicopathological features. Chemoradiation therapy is commonly employed to improve the survivability of patients with advanced breast cancer. However, the treatment process is often accompanied by the development of drug resistance, which eventually leads to treatment failure. Metabolism reprogramming has been recognized as a mechanism of breast cancer resistance. In this study, we established a doxorubicin-resistant MCF-7 (MCF-7-D500) cell line through a series of long-term doxorubicin in vitro treatments. Our data revealed that MCF-7-D500 cells exhibited increased multiple-drug resistance, cancer stemness, and invasiveness compared with parental cells. We analyzed the metabolic profiles of MCF-7 and MCF-7-D500 cells through liquid chromatography−mass spectrometry. We observed significant changes in 25 metabolites, of which, 21 exhibited increased levels (>1.5-fold change and p < 0.05) and 4 exhibited decreased levels (<0.75-fold change and p < 0.05) in MCF-7 cells with doxorubicin resistance. These results suggest the involvement of metabolism reprogramming in the development of drug resistance in breast cancer, especially the activation of glycolysis, the tricarboxylic acid (TCA) cycle, and the hexamine biosynthesis pathway (HBP). Furthermore, most of the enzymes involved in glycolysis, the HBP, and the TCA cycle were upregulated in MCF-7-D500 cells and contributed to the poor prognosis of patients with breast cancer. Our findings provide new insights into the regulation of drug resistance in breast cancer, and these drug resistance-related metabolic pathways can serve as targets for the treatment of chemoresistance in breast cancer.

Complete Mitochondrial Genome of Contracaecum Sp. (Nematoda: Ascarididae) from Night Herons in China.

Contracaecum species are zooparasitic anisakid nematodes and occur in gastrointestinal tracts of vertebrate/invertebrate animals, including humans, causing gastrointestinal pain, diarrhea, and increasingly severe vomiting. Although the complete mitochondrial (mt) genome (mitogenome) of Contracaecum sp. isolated from night herons in Beijing has been reported, the detailed information about this mt sequence is still puzzling. In the present study, we described the detailed characteristics across the complete mt DNA of Contracaecum sp., which includes 36 genes consisting of 12 protein genes, 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and 2 noncoding regions (NCRs), and all genes have the same orientation of transcription. The AT content in the complete mitogenome of Contracaecum sp. was 72.2%, and it was the least value (66.7%) in the cox1 gene but was the highest rate (84.1%) in NCRs. The highest nucleotide diversity (Pi) among the genus Contracaecum was nad4 (0.190) and the least was cox1 (0.125), which indicates that nad4 might have the potential ability as useful markers to detect cryptic species in the genus Contracaecum or subspecies. Based on the maximum likelihood (ML) and Bayesian inference (BI) computational algorithms within subfamilies Ascaridoidea and Heterakoidea, the results supported that Contracaecum sp. was a new species and the family Ascaridiidae was paraphyletic. The complete mitogenome sequence of Contracaecum sp. supported a clear recognition of Contracaecum species and provided the potential existence of cryptic species in the genus Contracaecum. Our findings would better contribute to the surveillance, molecular epidemiology, and control of Contracaecum.

[Research progress on Piperis Longi Fructus and predictive analysis of its quality markers].

Piperis Longi Fructus, made from the mature and immature fruit spikes of Piper longum, is a commonly used Mongolian medicine. In recent years, researchers have gradually deepened the research on ethnic medicines and found that Piperis Longi Fructus has significant effects in adjusting blood lipids and anti-cancer. Its new chemical components and pharmacological activities are also constantly updated. Subsequently, the development and application of Piperis Longi Fructus have attracted extensive attention. Thus, it is quite urgent to establish and improve a quality evaluation system for the medicine. On the basis of summarizing the chemical components and pharmacological effects of Piperis Longi Fructus and understanding the new concept of quality marker(Q-marker), the components which can be used as its Q-markers were analyzed from the aspects of the genetic relationship, traditional medicinal effects and properties, rules of compounding and compatibility, absorbed components and testability. The research can provide reference for the establishment of a quality evaluation system for Piperis Longi Fructus.

[Mechanism of Syringa oblata in treating angina pectoris based on GC-MS and network pharmacology].

The chemical constituents in the volatile oil of Syringa oblata were identified using GC-MS and NIST database. TCMSP and SwissTargetPrediction were employed to predict the potential targets of the active components in S. oblata. Through Online Mendelian Inheritance in Man(OMIM), GeneCards, and Kyoto Encyclopedia of Genes and Genomes(KEGG), we screened out the targets related to the prevention or treatment of angina pectoris by the volatile oil of S. oblata, and then used DAVID 6.8 to annotate the gene ontology(GO) terms and KEGG pathways. The "active components-targets-pathways" network was constructed in Cytoscape 3.6.0, and the key active components and targets of S. oblata were verified by Discovery Studio 2016. Forty-six chemical constituents were identified from the volatile oil of S. oblata; 198 potential targets of the active components and 1 138 targets associated with angina pectoris were predicted. A total of 71 common targets were shared by the active components and the disease, including cytochrome P450 19 A1(CYP19 A1) and prostaglandin G/H synthase 2(PTGS2). The KEGG pathways involved include PPAR, JAK-STAT, TNF, Toll-like receptor and NOD-like receptor signaling pathways. The active components in the volatile oil of S. oblata may play anti-inflammatory and anti-apoptosis roles. This study provides a reliable clue for further explanation of the effective components and the functioning mechanism of S. oblata in the treatment of angina pectoris.

Desensitization of NMDA channels requires ligand binding to both GluN1 and GluN2 subunits to constrict the pore beside the activation gate.

N-methyl-D-aspartate (NMDA) receptor channels are activated by glutamate (or NMDA) and glycine. The channels also undergo desensitization, which denotes decreased channel availability, after prolonged exposure to the activating ligands. Glycine apparently has a paradoxical negative effect on desensitization, as the increase in ambient glycine in concentrations required for channel activation would increase sustained NMDA receptor currents. We hypothesized that this classical "glycine-dependent desensitization" could be glycine-dependent activation in essence. By performing electrophysiological recordings and biophysical analyses with rat brain NMDA receptors heterogeneously expressed in Xenopus laevis oocytes, we characterized that the channel opened by "only" NMDA (in nominally glycine-free condition probably with the inevitable nanomolar glycine) would undergo a novel form of deactivation rather than desensitization, and is thus fully available for subsequent activation. Moreover, external tetrapentylammonium ions (TPentA), tetrabutylammonium ions, and tetrapropylammonium ions (TPA, in higher concentrations) block the pore and prohibit channel desensitization with a simple "foot-in-the-door" hindrance effect. TpentA and TPA have the same voltage dependence but show different flow dependence in binding affinity, revealing a common binding site at an electrical distance of ~0.7 from the outside yet differential involvement of the flux-coupling region in the external pore mouth. The smaller tetraethylammonium ion and the larger tetrahexylammonium and tetraheptylammonium ions may block the channel but could not affect desensitization. We conclude that NMDA receptor desensitization requires concomitant binding of both glycine and glutamate, and thus movement of both GluN1 and GluN2 subunits. Desensitization gate itself embodies a highly restricted pore reduction with a physical distance of ~4 Å from the charged nitrogen atom of bound tetraalkylammonium ions, and is located very close to the activation gate in the bundle-crossing region in the external pore vestibule.