Genomes of the Banyan Tree and Pollinator Wasp Provide Insights into Fig-Wasp Coevolution.

Banyan trees are distinguished by their extraordinary aerial roots. The Ficus genus includes species that have evolved a species-specific mutualism system with wasp pollinators. We sequenced genomes of the Chinese banyan tree, F. microcarpa, and a species lacking aerial roots, F. hispida, and one wasp genome coevolving with F. microcarpa, Eupristina verticillata. Comparative analysis of the two Ficus genomes revealed dynamic karyotype variation associated with adaptive evolution. Copy number expansion of auxin-related genes from duplications and elevated auxin production are associated with aerial root development in F. microcarpa. A male-specific AGAMOUS paralog, FhAG2, was identified as a candidate gene for sex determination in F. hispida. Population genomic analyses of Ficus species revealed genomic signatures of morphological and physiological coadaptation with their pollinators involving terpenoid- and benzenoid-derived compounds. These three genomes offer insights into and genomic resources for investigating the geneses of aerial roots, monoecy and dioecy, and codiversification in a symbiotic system.

Clinical characteristics of post-stroke basal ganglia aphasia and the study of language-related white matter tracts based on diffusion spectrum imaging.

BACKGROUND: Stroke often damages the basal ganglia, leading to atypical and transient aphasia, indicating that post-stroke basal ganglia aphasia (PSBGA) may be related to different anatomical structural damage and functional remodeling rehabilitation mechanisms. The basal ganglia contain dense white matter tracts (WMTs). Hence, damage to the functional tract may be an essential anatomical structural basis for the development of PSBGA. METHODS: We first analyzed the clinical characteristics of PSBGA in 28 patients and 15 healthy controls (HCs) using the Western Aphasia Battery and neuropsychological test batteries. Moreover, we investigated white matter injury during the acute stage using diffusion magnetic resonance imaging scans for differential tractography. Finally, we used multiple regression models in correlation tractography to analyze the relationship between various language functions and quantitative anisotropy (QA) of WMTs. RESULTS: Compared with HCs, patients with PSBGA showed lower scores for fluency, comprehension (auditory word recognition and sequential commands), naming (object naming and word fluency), reading comprehension of sentences, Mini-Mental State Examination, and Montreal Cognitive Assessment, along with increased scores in Hamilton Anxiety Scale-17 and Hamilton Depression Scale-17 within 7 days after stroke onset (P < 0.05). Differential tractography revealed that patients with PSBGA had damaged fibers, including in the body fibers of the corpus callosum, left cingulum bundles, left parietal aslant tracts, bilateral superior longitudinal fasciculus II, bilateral thalamic radiation tracts, left fornix, corpus callosum tapetum, and forceps major, compared with HCs (FDR < 0.02). Correlation tractography highlighted that better comprehension was correlated with a higher QA of the left inferior fronto-occipital fasciculus (IFOF), corpus callosum forceps minor, and left extreme capsule (FDR < 0.0083). Naming was positively associated with the QA of the left IFOF, forceps minor, left arcuate fasciculus, and uncinate fasciculus (UF) (FDR < 0.0083). Word fluency of naming was also positively associated with the QA of the forceps minor, left IFOF, and thalamic radiation tracts (FDR < 0.0083). Furthermore, reading was positively correlated with the QA of the forceps minor, left IFOF, and UF (FDR < 0.0083). CONCLUSION: PSBGA is primarily characterized by significantly impaired word fluency of naming and preserved repetition abilities, as well as emotional and cognitive dysfunction. Damaged limbic pathways, dorsally located tracts in the left hemisphere, and left basal ganglia pathways are involved in PSBGA pathogenesis. The results of connectometry analysis further refine the current functional localization model of higher-order neural networks associated with language functions.

Novel mutation in EFEMP1 identified from two Chinese POAG families differentially activated endoplasmic reticulum stress markers and induced glaucoma in mouse.

Primary open-angle glaucoma (POAG) is the most common type of glaucoma. Using whole-exome sequencing, we identified two independent families diagnosed as POAG from the China with a novel EFEMP1 variant (Exon3, c.175A>C p.Met59Leu); Three previously reported variants c.1160G>A p.R387Q, c.1189T>C p.Y397H, and c.1429C>T p.R477C in EFEPM1 from 55 sporadic POAG individuals were also identified. The variant c.175A>C p.Met59Leu co-segregated with the disease phenotype within the families. Immunoprecipitation and western blot assays showed that all three EFEMP1 mutants (p.Met59Leu, pArg140Trp, pArg345Trp) increased intracellular protein aggregations, and pMet59Leu and pArg140Arg also enhanced their extracellular proteins secretion, compared to WT in HEK293T. The differential regulations to endoplasmic reticulum (ER) stress markers ATF4, GPR78/94, and CHOP, and differential phosphorylation activations to CREB at Ser133, AKT at Ser473, p44/42 at Thr202/Tyr204, and STAT3 at Tyr705, were also detected among the mutants and WT. Finally, we revealed a significant increment of intraocular pressure and obvious reduction of RGC cells at the sixth week following intravitreal injection of adenovirus 5 (Ad5) expressing in pMet59Leu compared to WT and GFP controls. Together, variant c.175A>C p.Met59Leu in EFEMP1 is pathogenic and different mutants in EFEMP1 triggered distinct signaling pathways, explaining the reason of mutation-dependent disease phenotypes of EFEMP1.

miR-155 promotes Th17 differentiation by targeting FOXP3 to aggravate inflammation in MRSA pneumonia.

BACKGROUND: Previous researches have clarified that miR-155 is increased in methicillin-resistant Staphylococcus aureus (MRSA) pneumonia, and modulates Th9 differentiation. Like Th9 cells, Th17 cells were also a subset of CD4+ T cells and involved in MRSA pneumonia progression. This work aimed to investigate the role and mechanism of miR-155 in Th17 differentiation. METHODS: Bronchoalveolar lavage fluid (BALF) was collected from children with MRSA pneumonia and bronchial foreign bodies. MRSA-infected murine model was established followed by collecting BALF and lung tissues. qRT-PCR, ELISA and flow cytometry were performed to examine the mRNA expression and concentration of IL-17 and the number of Th17 cells in above samples. HE and ELISA were used to evaluate inflammatory responses in lung. Furthermore, CD4+ T cells were isolated from BALF of children for in vitro experiments. After treatments with miR-155 mimic/inhibitor, the roles of miR-155 in Th17/IL-17 regulation were determined. The downstream of miR-155 was explored by qRT-PCR, western blotting, dual luciferase reporter analysis and RIP assay. RESULTS: The levels of IL-17 and the proportion of Th17 cells were increased in children with MRSA pneumonia. A similar pattern was observed in MRSA-infected mice. On the contrary, IL-17 neutralization abolished the activation of Th17/IL-17 induced by MRSA infection. Furthermore, IL-17 blockade diminished the inflammation caused by MRSA. In vitro experiments demonstrated miR-155 positively regulated IL-17 expression and Th17 differentiation. Mechanistically, FOXP3 was a direct target of miR-155. miR-155 inhibited FOXP3 level via binding between FOXP3 and Argonaute 2 (AGO2), the key component of RNA-induced silencing complex (RISC). FOXP3 overexpression reversed elevated IL-17 levels and Th17 differentiation induced by miR-155. CONCLUSIONS: miR-155 facilitates Th17 differentiation by reducing FOXP3 through interaction of AGO2 and FOXP3 to promote the pathogenesis of MRSA pneumonia. IL-17 blockade weakens the inflammation due to MRSA, which provides a nonantibiotic treatment strategy for MRSA pneumonia.

Clinical outcomes and synergistic effect between radiotherapy and immunotherapy in patients with extensive-stage small cell lung cancer: a real-world study.

BACKGROUND: Patients with extensive-stage small cell lung cancer (ES-SCLC) experience significant therapeutic challenges and limited survival rates. This study aimed to investigate the efficacy of combining immunotherapy (IT) with chemotherapy (CT) for treating ES-SCLC and to explore the synergistic effect between radiotherapy (RT) and IT. METHODS: This retrospective analysis examined patients with ES-SCLC who received treatment at three centers. Furthermore, propensity score-matched (PSM) analysis was conducted. The Kaplan‒Meier method and Cox proportional hazards regression were used to compare the survival outcomes. RESULTS: A total of 257 eligible patients with ES-SCLC were included in the analysis. Among all patients, the median overall survival (mOS) was 18.0 m in the chemoimmunotherapy (CT + IT) group and 15.7 m in the CT group (p = 0.208). The median real-world progression-free survival (mrwPFS) was 7.7 m and 6.8 m (p = 0.043) in the CT + IT and CT group, respectively. Moreover, the mOS was 22.0 m in the chemoradiotherapy (CT + RT) group and 13.6 m in the CT group (p < 0.001). The mrwPFS was 7.4 m and 6.0 m (p = 0.175) in the CT + RT group and CT group, respectively. The multivariate analyses revealed that sex, liver metastasis and RT were independent prognostic factors for OS (p < 0.05), while liver metastasis and IT were found to be independent predictive factors of real-world progression-free survival (rwPFS) (p < 0.05). After PSM, the mOS was 23.2 m in the CT + IT group and 13.0 m in the CT group (p = 0.008). The mrwPFS was 7.3 m and 6.2 m (p = 0.096) in the CT + IT group and the CT group, respectively. Moreover, the mOS was 21.4 m in the CT + RT group and 12.5 m in the CT group (p < 0.001). The mrwPFS was 7.3 m and 5.2 m (p = 0.220) in the CT + RT group and the CT group, respectively. Additionally, our study revealed that in the PD-1 group, RT significantly improved patient survival (36.0 m vs. 15.8 m, p = 0.041). CONCLUSION: An increasing number of treatment options are being explored for ES-SCLC, and CT is the cornerstone of treatment for this disease. Combining CT with IT and RT has demonstrated remarkable efficacy and excellent safety profiles, and such treatments are worthy of further exploration.

IL-4-secreting CD40L+ MAIT cells support antibody production in the peripheral blood of Heonch-Schönlein purpura patients.

OBJECTIVE: Here, we explored the phenotype and function of MAIT cells in the peripheral blood of patients with HSP. METHODS: Blood samples from HSP patients and HDs were assessed by flow cytometry and single-cell RNA sequencing to analyze the proportion, phenotype, and function of MAIT cells. Th-cytokines in the serum of HSP patients were analyzed by CBA. IgA in cocultured supernatant was detected by CBA to analyze antibody production by B cells. RESULTS: The percentage of MAIT cells in HSP patients was significantly reduced compared with that in HDs. Genes related to T cell activation and effector were up-regulated in HSP MAIT cells, indicating a more activated phenotype. In addition, HSP MAIT cells displayed a Th2-like profile with the capacity to produce more IL-4 and IL-5, and IL-4 was correlated with IgA levels in the serum of HSP patients. Furthermore, CD40L was up-regulated in HSP MAIT cells, and CD40L+ MAIT cells showed an increased ability to produce IL-4 and to enhance IgA production by B cells. CONCLUSION: Our data demonstrate that MAIT cells in HSP patients exhibit an activated phenotype. The enhanced IL-4 production and CD40L expression of MAIT cells in HSP patients could take part in the pathogenesis of HSP.

Are children with IgA nephropathy different from adult patients?

BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.

Catalytic PMS oxidation universality of CuFe2O4/MnO2 heterojunctions at multiple application scenarios.

The magnetic CuFe2O4/MnO2 heterojunctions were prepared by hydrothermal method, and the effect of different reaction temperature on the physicochemical properties and catalytic activity was investigated. The CuFe2O4/MnO2 heterojunctions prepared at 100 °C can effectively activate peroxymonosulfate (PMS) at multiple application scenarios for degradation and mineralization of tetracycline, o-nitrophenol and ceftriaxone sodium under indoor light, visible light and dark condition. Additionally, the CuFe2O4/MnO2-PMS system showed high catalytic activity and anti-interference ability for degradation of pharmaceutical pollutants in natural water bodies and industrial wastewater. The TC removal efficiency in Qianhu Lake water, Ganjiang River water and tap water was about 88%, 92% and 89%, respectively. The CuFe2O4/MnO2-PMS system is also effective for actual pharmaceutical wastewater treatment with 77.9% of COD removal efficiency. Interestingly, the reactive species of CuFe2O4/MnO2-PMS system under visible light are different from those in dark condition, and the different catalytic mechanisms at multiple application scenarios were proposed. This work provides new insights into mechanism exploration of heterojunction catalyst for PMS activation.

Comparative Analysis of Intestinal TLR4 Gene Expression and Functional Verification in Lepus yarkandensis and Oryctolagus cuniculus.

Lepus yarkandensis live year-round in harsh desert environments and are less susceptible to enteritis. The living conditions of Oryctolagus cuniculus in captivity were suitable, but they were highly susceptible to death by Gram-negative bacteria infected with inflammatory bowel disease complex.TLR4 is closely related to the occurrence of enteritis, and the neighbor-joining topology based on the 12S rDNA sequences showed that the relationship between O. cuniculus and L. yarkandensis is as high as 98%.Therefore, we chose O. cuniculus and L. yarkandensis for comparative study.The purpose of this study was to investigate the role of Toll-like receptor 4 (TLR4) in the regulation of immunity and inflammation in the intestinal tract of L. yarkandensis. In this study, the TLR4 gene was cloned for the first time in the colon of L. yarkandensis. The expression of TLR4 in the intestinal tissues of L. yarkandensis and O. cuniculus was detected by histological observation, real-time fluorescence quantification PCR(qRT-PCR), and protein blotting (Western blot).An LPS-induced cell inflammation model was constructed in vitro, and ELISA was used to examine the effect of pEGFP-N1-TLR4 and siRNA knockout on the anti-inflammatory ability of the TLR4 gene. The results showed that the open reading frame of the L. yarkandensis TLR4 gene was 2520 bp in length. Compared with the sequence of O. cuniculus, there were 15 differences in the TLR4 amino acid sequence of L. yarkandensis, 12 of which occurred in the LRR domain and 2 in the TIR domain, and the sequence changed from G to D at position 298. Immunohistochemistry showed that TLR4 was mainly expressed in the epithelial cells of the colon L. yarkandensis, and the expression level of TLR4 in the cecum and colon was significantly lower compared with that of O. cuniculus. qRT-PCR and Western blot results showed that the expression level of TLR4 in the colon of L. yarkandensis was significantly lower than that of O. cuniculus. At the cellular level, ELISA showed that overexpression of the TLR4 protein in L. yarkandensis could reduce the LPS-induced inflammatory response. Therefore, according to the above results, the protein structure and function of L. yarkandensis TLR4 may be different due to the change of nucleotide, which affects its binding with LPS and the activation of downstream molecules, so that L. yarkandensis is not prone to enteritis and can adapt to the harsh desert environment for a long time. This study also laid the foundation for improving the disease resistance of O. cuniculus and promoting the development and utilization of genes in L. yarkandensis.

Semi-permeable membrane-covered high-temperature aerobic composting: A review.

Semi-permeable membrane-covered high-temperature aerobic composting (SMHC) is a suitable technology for the safe treatment and disposal of organic solid waste as well as for improving the quality of the final compost. This paper presents a comprehensive summary of the impact of semi-permeable membranes centered on expanded polytetrafluoroethylene (e-PTFE) on compost physicochemical properties, carbon and nitrogen transformations, greenhouse gas emission reduction, microbial community succession, antibiotic removal, and antibiotic resistance genes migration. It is worth noting that the semi-permeable membrane can form a micro-positive pressure environment under the membrane, promote the uniform distribution of air in the heap, reduce the proportion of anaerobic area in the heap, improve the decomposition rate of organic matter, accelerate the decomposition of compost and improve the quality of compost. In addition, this paper presents several recommendations for future research areas in the SMHC. This investigation aims to guide for implementation of semi-permeable membranes in high-temperature aerobic fermentation processes by systematically compiling the latest research progress on SMHC.

Prostate magnetic resonance imaging-targeted biopsy global grade correlates better than highest grade with prostatectomy grade.

BACKGROUND: Magnetic resonance imaging (MRI)-targeted prostate biopsy has become an increasingly common method of diagnosing prostate cancer. A previous study from our institution demonstrated that the biopsy global Grade Group (gGG, aggregate GG of all positive cores) and highest Grade Group (hGG in any core) both show substantial concordance with the Grade Group at radical prostatectomy (RPGG) while the discordance predominantly consists of upgrading in gGG and downgrading in hGG. We performed a larger cohort study focused on biopsy cases in which gGG and hGG differ, to determine their relative concordance with RPGG. METHODS: We conducted a retrospective review of radical prostatectomy specimens with prior MRI-targeted biopsies from our institution between 2016 and 2020. Separate gGG and hGG were assigned to each MRI-targeted lesion. Targeted lesions with different gGG versus hGG were segregated from those with identical gGG and hGG. The concordance of biopsy GG with RPGG was evaluated using κ coefficient analysis. RESULTS: Of the 489 lesions with MRI-targeted biopsies, 82 (17%) differed in gGG versus hGG. The gGG of 46 (56%), 33 (40%), and 3 (4%) lesions were unchanged, upgraded, and downgraded at radical prostatectomy, respectively (κ= 0.302, weighted κ = 0.334). The hGG of 24 (29%), 9 (11%), and 49 (60%) lesions were unchanged, upgraded, and downgraded at radical prostatectomy, respectively (κ = 0.040, weighted κ = 0.198). When stratified by the biopsy GG, gGG showed the highest concordance in GG2 (61%) and GG3 (54%) lesions. The hGG resulted in substantial downgrading (60%) with less optimal concordance regardless of the biopsy GG. Neither the prebiopsy prostate specific antigen level nor the PI-RADS score was predictive of upgrading of gGG. CONCLUSIONS: When gGG and hGG differ, gGG method more accurately predicts the RPGG than hGG, particularly in GG2 and GG3 lesions which comprised the majority of targeted lesions.

Stimulated Raman histology, a novel method to allow for rapid pathologic examination of unprocessed, fresh prostate biopsies.

INTRODUCTION: Delay between targeted prostate biopsy (PB) and pathologic diagnosis can lead to a concern of inadequate sampling and repeated biopsy. Stimulated Raman histology (SRH) is a novel microscopic technique allowing real-time, label-free, high-resolution microscopic images of unprocessed, unsectioned tissue. This technology holds potential to decrease the time for PB diagnosis from days to minutes. We evaluated the concordance of pathologist interpretation of PB SRH as compared with traditional hematoxylin and eosin (H&E) stained slides. METHODS: Men undergoing prostatectomy were included in an IRB-approved prospective study. Ex vivo 18-gauge PB cores, taken from prostatectomy specimen, were scanned in an SRH microscope (NIO; Invenio Imaging) at 20 microns depth using two Raman shifts: 2845 and 2930 cm-1 , to create SRH images. The cores were then processed as per normal pathologic protocols. Sixteen PB containing a mix of benign and malignant histology were used as an SRH training cohort for four genitourinary pathologists, who were then tested on a set of 32 PBs imaged by SRH and processed by traditional H&E. Sensitivity, specificity, accuracy, and concordance for prostate cancer (PCa) detection on SRH relative to H&E were assessed. RESULTS: The mean pathologist accuracy for the identification of any PCa on PB SRH was 95.7%. In identifying any PCa or ISUP grade group 2-5 PCa, a pathologist was independently able to achieve good and very good concordance (κ: 0.769 and 0.845, respectively; p < 0.001). After individual assessment was completed a pathology consensus conference was held for the interpretation of the PB SRH; after the consensus conference the pathologists' concordance in identifying any PCa was also very good (κ: 0.925, p < 0.001; sensitivity 95.6%; specificity 100%). CONCLUSION: SRH produces high-quality microscopic images that allow for accurate identification of PCa in real-time without need for sectioning or tissue processing. The pathologist performance improved through progressive training, showing that ultimately high accuracy can be obtained. Ongoing SRH evaluation in the diagnostic and treatment setting hold promise to reduce time to tissue diagnosis, while interpretation by convolutional neural network may further improve diagnostic characteristics and broaden use.

Single-cell analysis of localized prostate cancer patients links high Gleason score with an immunosuppressive profile.

BACKGROUND: Evading immune surveillance is a hallmark for the development of multiple cancer types. Whether immune evasion contributes to the pathogenesis of high-grade prostate cancer (HGPCa) remains an area of active inquiry. METHODS: Through single-cell RNA sequencing and multicolor flow cytometry of freshly isolated prostatectomy specimens and matched peripheral blood, we aimed to characterize the tumor immune microenvironment (TME) of localized prostate cancer (PCa), including HGPCa and low-grade prostate cancer (LGPCa). RESULTS: HGPCa are highly infiltrated by exhausted CD8+ T cells, myeloid cells, and regulatory T cells (TRegs). These HGPCa-infiltrating CD8+ T cells expressed high levels of exhaustion markers including TIM3, TOX, TCF7, PD-1, CTLA4, TIGIT, and CXCL13. By contrast, a high ratio of activated CD8+  effector T cells relative to TRegs and myeloid cells infiltrate the TME of LGPCa. HGPCa CD8+  tumor-infiltrating lymphocytes (TILs) expressed more androgen receptor and prostate-specific membran antigen yet less prostate-specific antigen than the LGPCa CD8+  TILs. The PCa TME was infiltrated by macrophages but these did not clearly cluster by M1 and M2 markers. CONCLUSIONS: Our study reveals a suppressive TME with high levels of CD8+ T cell exhaustion in localized PCa, a finding enriched in HGPCa relative to LGPCa. These studies suggest a possible link between the clinical-pathologic risk of PCa and the associated TME. Our results have implications for our understanding of the immunologic mechanisms of PCa pathogenesis and the implementation of immunotherapy for localized PCa.

Improving feature selection performance for classification of gene expression data using Harris Hawks optimizer with variable neighborhood learning.

Gene expression profiling has played a significant role in the identification and classification of tumor molecules. In gene expression data, only a few feature genes are closely related to tumors. It is a challenging task to select highly discriminative feature genes, and existing methods fail to deal with this problem efficiently. This article proposes a novel metaheuristic approach for gene feature extraction, called variable neighborhood learning Harris Hawks optimizer (VNLHHO). First, the F-score is used for a primary selection of the genes in gene expression data to narrow down the selection range of the feature genes. Subsequently, a variable neighborhood learning strategy is constructed to balance the global exploration and local exploitation of the Harris Hawks optimization. Finally, mutation operations are employed to increase the diversity of the population, so as to prevent the algorithm from falling into a local optimum. In addition, a novel activation function is used to convert the continuous solution of the VNLHHO into binary values, and a naive Bayesian classifier is utilized as a fitness function to select feature genes that can help classify biological tissues of binary and multi-class cancers. An experiment is conducted on gene expression profile data of eight types of tumors. The results show that the classification accuracy of the VNLHHO is greater than 96.128% for tumors in the colon, nervous system and lungs and 100% for the rest. We compare seven other algorithms and demonstrate the superiority of the VNLHHO in terms of the classification accuracy, fitness value and AUC value in feature selection for gene expression data.

Effect of different doses of dexmedetomidine on the median effective concentration of propofol during gastrointestinal endoscopy: a randomized controlled trial.

AIMS: Dexmedetomidine could be an ideal adjuvant to propofol during gastrointestinal endoscopy because it provides both analgesia and sedation without respiratory depression. This study investigates the effect of different doses of dexmedetomidine on the median effective concentration of propofol during gastrointestinal endoscopy. METHODS: Ninety adult patients were randomly assigned to Group Control, Group DEX0.5 (0.5 µg/kg dexmedetomidine) or Group DEX1.0 (1.0 µg/kg dexmedetomidine). Anaesthesia during endoscopy was implemented by plasma target-controlled infusion (TCI) of propofol with different doses of dexmedetomidine. TCI concentration of the first patient for each group was 2.5 µg/mL and the consecutive adjacent concentration gradient was 0.5 µg/mL. Median effective concentration (EC50 ) of propofol by TCI for gastrointestinal endoscopy was determined by using the modified Dixon's up-and-down method. Cardiovascular variables were also measured. RESULTS: EC50 of propofol by TCI and 95% confidence interval (CI) for gastrointestinal endoscopy were 3.77 (3.48-4.09), 2.51 (2.27-2.78) and 2.10 (1.90-2.33) µg/mL in Group Control, Group DEX0.5 and Group DEX1.0, respectively. The average percent change from heart rate (HR) baseline was 2.8 (8.9), -7.4 (7.7) and -10.5 (8.8) (P < .001), and the average percent change from mean arterial pressure (MAP) baseline was -10.6 [-24.7; 3.5], -9.5 [-29.2; 11.4] and -4.0 [-27.3; 15.5] (P = .034) in Group Control, Group DEX0.5 and Group DEX1.0, respectively. CONCLUSIONS: Dexmedetomidine reduced the EC50 of propofol by TCI. A 0.5-1 µg/kg dose of dexmedetomidine caused a decrease in HR without bradycardia. The decrease in dosage of propofol with increasing doses of dexmedetomidine caused more stable MAP. Dexmedetomidine is an ideal adjuvant drug to propofol during gastrointestinal endoscopy.

High glucose promotes podocyte movement: From the perspective of single cell motility assay.

Podocytes are highly specialized glomerular epithelial cells that play a crucial role in maintaining the glomerular filtration barrier, impairment of which usually leads to proteinuria. The phenotypic alterations of podocytes are described to be one of the critical mechnisms underlying podocyte detachment from the glomerular basement membrane. High glucose is the major factor mediating the renal damages and podocyte injuries in the process of diabetic nephropathy. It was revealed that high glucose stimulated the epithelial-to-mesenchymal transition of podocyte, thus contributing to proteinuria. When the podocytes converse from epithelial phenotype to mesenchymal phenotype, their migratory capacity significantly increases. Previously, cell migration is conventionally detected by the wound healing assay and the transwell assay. In this study, we investigated and comfirmed the possibility of using single cell motility assay for the anaysis of podocyte motility under high glucose condtition.

HIF-1α drives the transcription of NOG to inhibit osteogenic differentiation of periodontal ligament stem cells in response to hypoxia.

Osteogenic differentiation of periodontal ligament stem cells (PDLSCs) is limited in hypoxia, and HIF-1α is key to the response to hypoxia. However, its mechanisms remain largely unknown. This study discovered an osteogenesis-related gene sensitive to hypoxia in PDLSCs, and investigated the molecular mechanisms between HIF-1α and the gene. NOG, a gene that negatively regulates osteogenesis, was discovered by RNA-seq. Under normoxic conditions, HIF-1α overexpression led to enhanced expression of NOG/Noggin and inhibited the expression of osteogenesis-related genes, while inhibition of HIF-1α reversed this effect. The expression of HIF-1α, NOG/Noggin and the osteogenesis-related genes were detected by qRT-PCR or Western blot. Mechanistically, we verified that HIF-1α binds to the hypoxia response element (-1505 to -1502) in the promotor of NOG to enhance secretion of Noggin by chromatin immunoprecipitation and a dual-luciferase reporter assay. IHC staining findings in an animal model verified that Noggin-associated osteogenic differentiation was inhibited in hypoxia. NOG displayed a concordant relationship with HIF-1α, and secreted more with increasing of HIF-1α. Hypoxia stabilized HIF-1α, which bound to the HRE (-1505 to -1502) of the NOG promotor to enhance NOG transcription resulted in inhibiting osteogenic differentiation of PDLSCs. This study offers a promising therapy for periodontitis.

Correlation between negative life events and suicide attempts among Yi adolescents with HIV/AIDS in Liangshan Prefecture.

OBJECTIVE: To investigate the incidence of suicide attempts among adolescents with HIV/AIDS in Liangshan Prefecture, Sichuan Province, as well as the correlation between negative life events, sleep, exercise, drug therapy and suicide attempts. METHODS: A total of 180 Yi adolescents aged 11-19 years with HIV/AIDS in a county of Liangshan Prefecture, Sichuan Province, China, were investigated by census. The main outcome indicators included the incidence of suicide attempts and whether negative life events, sleep, exercise, drug therapy and other factors were related to suicide attempts. RESULTS: We found that the incidence rate of suicide attempts among Yi adolescents with HIV/AIDS in Liangshan Prefecture was 13.9%. Negative life events were a risk factor for suicide attempts (OR = 1.047, p < 0.001, 95% CI 1.027-1.067). In the factors of negative life events, adaptation was a risk factor for suicide attempts (OR = 1.203, p = 0.026, 95% CI 1.022-1.416), and academic pressure showed a tendency to be a risk factor for suicide attempts (OR = 1.149, p = 0.077, 95% CI 0.985-1.339). However, the punishment factor, interpersonal stress factor and loss factor had no significant correlation with suicide attempts. There was no significant correlation between sleep, exercise, drug therapy and suicide attempts. CONCLUSION: The proportion of suicide attempts among Yi adolescents with HIV/AIDS in Liangshan Prefecture is high and should be considered. Negative life events are independent risk factors for suicide attempts, and it is necessary to strengthen the screening and early intervention for suicide attempts in HIV/AIDS adolescents with definite negative life events.

Design, Synthesis, Antifungal Activity, and Molecular Docking of Streptochlorin Derivatives Containing the Nitrile Group.

Based on the structures of natural products streptochlorin and pimprinine derived from marine or soil microorganisms, a series of streptochlorin derivatives containing the nitrile group were designed and synthesized through acylation and oxidative annulation. Evaluation for antifungal activity showed that compound 3a could be regarded as the most promising candidate-it demonstrated over 85% growth inhibition against Botrytis cinerea, Gibberella zeae, and Colletotrichum lagenarium, as well as a broad antifungal spectrum in primary screening at the concentration of 50 µg/mL. The SAR study revealed that non-substituent or alkyl substituent at the 2-position of oxazole ring were favorable for antifungal activity, while aryl and monosubstituted aryl were detrimental to activity. Molecular docking models indicated that 3a formed hydrogen bonds and hydrophobic interactions with Leucyl-tRNA Synthetase, offering a perspective for the possible mechanism of action for antifungal activity of the target compounds.

Identification of in vivo metabolites of Citri Sarcodactylis Fructus by UHPLC-Q/Orbitrap HRMS.

INTRODUCTION: Citri Sarcodactylis Fructus has the effects of relieving cough, removing phlegm, and reducing asthma, but little is known about the metabolic and distribution of its chemical constituents in vivo. Therefore, it is necessary to study the metabolism of Citri Sarcodactylis Fructus in vivo. OBJECTIVE: We aimed to (1) analyze the distribution of prototype compounds and metabolites of the chemical constituents of Citri Sarcodactylis Fructus in rat and (2) infer the metabolites and metabolic pathways of the chemical constituents. MATERIALS AND METHODS: A C18 column (3 × 100 mm, 2.6 µm) was used. The mobile phase was water containing 0.1% formic acid (eluent A) and acetonitrile containing 0.1% formic acid (eluent B) at a discharge rate of 0.3 mL/min. Mass spectra of biological samples were collected in electrospray ionization (ESI) positive ion mode in the m/z 100-1500 scan range. The obtained biological samples were then subjected to chemical analysis, including plasma, urine, feces, and heart, liver, spleen, lungs, kidneys, stomach, and small intestine tissues. Prototype compounds and metabolites were identified. RESULTS: In all, 40 prototype compounds and 78 metabolites, including 26 phase I metabolites and 52 phase II metabolites, were identified using UHPLC-Q/Orbitrap HRMS. Eight possible metabolic pathways (reduction, hydrolysis, dehydration, methylation, hydroxylation, sulfation, glucuronidation, and demethylation) were proposed. The prototype compounds were predominantly distributed in lung tissues. The metabolites were mainly distributed in plasma and kidney tissues. CONCLUSION: We systematically investigated the metabolites of Citri Sarcodactylis Fructus in vivo. We suggest metabolic pathways that might be relevant for further metabolic studies and screening of active ingredients of Citrus Sarcodactylis Fructus in vivo.