Treponema pallidum-induced prostaglandin E2 secretion in skin fibroblasts leads to neuronal hyperpolarization: A cause of painless ulcers.

BACKGROUND: Primary syphilis is characterized by painless ulcerative lesions in the genitalia, the aetiology of painless remains elusive. OBJECTIVES: To investigate the role of Treponema pallidum in painless ulcer of primary syphilis, and the mechanisms underlying painless ulcers caused by T. pallidum. METHODS: An experimental rabbit model of primary syphilis was established to investigate its effects on peripheral nerve tissues. Human skin fibroblasts were used to examine the role of T. pallidum in modulating neurotransmitters associated with pain and to explore the signalling pathways related to neurotransmitter secretion by T. pallidum in vitro. RESULTS: Treponema pallidum infection did not directly lead to neuronal damage or interfere with the neuronal resting potential. Instead, it facilitated the secretion of prostaglandin E2 (PGE2) through endoplasmic reticulum stress in both rabbit and human skin fibroblasts, and upregulation of PGE2 induced the hyperpolarization of neurones. Moreover, the IRE1α/COX-2 signalling pathway was identified as the underlying mechanism by which T. pallidum induced the production of PGE2 in human skin fibroblasts. CONCLUSION: Treponema pallidum promotes PGE2 secretion in skin fibroblasts, leading to the excitation of neuronal hyperpolarization and potentially contributing to the pathogenesis of painless ulcers in syphilis.

Treponema pallidum protein Tp47 induced prostaglandin E2 to inhibit the phagocytosis in human macrophages.

BACKGROUND: During Treponema pallidum (T. pallidum) infection, the host's immune system actively engages in pursuit and elimination of T. pallidum, while T. pallidum skillfully employs various mechanisms to evade immune recognition. Macrophages exhibit incomplete clearance of T. pallidum in vitro and the underlying mechanism of how T. pallidum resists the attack of macrophage remains unclear. OBJECTIVES: To investigate the effect of T. pallidum membrane protein Tp47 on the phagocytosis of macrophages. METHODS: THP-1-derived macrophages were used to investigate the role of Tp47 in the secretion of Prostaglandin E2 (PGE2) in macrophages and the mechanism by which Tp47 induced the production of PGE2, as well as the impact of PGE2 on the macrophage's phagocytosis. RESULTS: Tp47 (1-10 µg/mL) significantly inhibited the phagocytosis of latex beads and T. pallidum in macrophages (p ≤ 0.05). PGE2 production by macrophages could be induced by Tp47, and the phagocytic function of macrophages could be restored using PGE2 antibody. Tp47 produced PGE2 by activating the PERK/NF-κB/COX-2 pathway in macrophages. Inhibitors targeting PERK, NF-κB and COX-2, respectively, reduced the level of PGE2 and restored the phagocytic function of macrophages. CONCLUSION: Tp47-induced PGE2 production via the PERK/NF-κB/COX-2 pathway contributed to macrophage phagocytosis inhibition, which potentially contributes to immune evasion during the T. pallidum infection.

Testosterone promotes the migration, invasion and EMT process of papillary thyroid carcinoma by up-regulating Tnnt1.

PURPOSE: To explore the key genes and molecular pathways in the progression of thyroid papillary carcinoma (PTC) promoted by testosterone using RNA-sequencing technology, and to provide new drug targets for improving the therapeutic effect of PTC. METHODS: Orchiectomy (ORX) was carried out to construct ORX mouse models. TPC-1 cells were subcutaneously injected for PTC formation in mice, and the tumor tissues were collected for RNA-seq. The key genes were screened by bioinformatics technology. Tnnt1 expression in PTC cells was knocked down or overexpressed by transfection. Cell counting kit-8 (CCK-8), colony formation assay, scratch assay and transwell assay were adopted, respectively, for the detection of cell proliferation, colony formation, migration and invasion. Besides, quantification real-time polymerase chain reaction (qRT-PCR) and western blot were utilized to determine the mRNA and protein expression levels of genes in tissues or cells. RESULTS: Both estradiol and testosterone promoted the growth of PTC xenografts. The key gene Tnnt1 was screened and obtained by bioinformatics technology. Functional analysis revealed that overexpression of Tnnt1 could markedly promote the proliferation, colony formation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) process of PTC cells, as well as could activate p38/JNK pathway. In addition, si-Tnt1 was able to inhibit the cancer-promoting effect of testosterone. CONCLUSION: Based on the outcomes of bioinformatics and basic experiments, it is found that testosterone can promote malignant behaviors such as growth, migration, invasion and EMT process of PTC by up-regulating Tnnt1 expression. In addition, the function of testosterone may be achieved by activating p38/JNK signaling pathway.

Tp47-Induced Monocyte-Derived Microvesicles Promote the Adherence of THP-1 Cells to Human Umbilical Vein Endothelial Cells via an ERK1/2-NF-κB Signaling Cascade.

The Treponema pallidum membrane protein Tp47 induces immunocyte adherence to vascular cells and contributes to vascular inflammation. However, it is unclear whether microvesicles are functional inflammatory mediators between vascular cells and immunocytes. Microvesicles that were isolated from Tp47-treated THP-1 cells using differential centrifugation were subjected to adherence assays to determine the adhesion-promoting effect on human umbilical vein endothelial cells (HUVECs). Intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) levels in Tp47-induced microvesicle (Tp47-microvesicle)-treated HUVECs were measured, and the related intracellular signaling pathways of Tp47-microvesicle-induced monocyte adhesion were investigated. Tp47-microvesicles promoted THP-1 cell adhesion to HUVECs (P < 0.01) and upregulated ICAM-1 and VCAM-1 expression in HUVECs (P < 0.001). The adhesion of THP-1 cells to HUVECs was inhibited by anti-ICAM-1 and anti-VCAM-1 neutralizing antibodies. Tp47-microvesicle treatment of HUVECs activated the extracellular signal-regulated kinase 1/2 (ERK1/2) and NF-κB signaling pathways, whereas ERK1/2 and NF-κB inhibition suppressed the expression of ICAM-1 and VCAM-1 and significantly decreased the adhesion of THP-1 cells to HUVECs. IMPORTANCE Tp47-microvesicles promote the adhesion of THP-1 cells to HUVECs through the upregulation of ICAM-1 and VCAM-1 expression, which is mediated by the activation of the ERK1/2 and NF-κB pathways. These findings provide insight into the pathophysiology of syphilitic vascular inflammation.

[Efficacy of high-voltage long-duration pulsed radiofrequency treatment in patients with neuralgia resulting from failed back surgery syndrome].

Objective: To explore the efficacy and safety of high-voltage long-duration pulsed radiofrequency (PRF) treatment in patients with neuralgia resulting from failed back surgery syndrome (FBSS). Methods: The clinical data of 58 patients diagnosed with neuralgia resulting from FBSS in the Department of Pain Medicine, Peking University Third Hospital from January 2017 to January 2020 were retrospectively analyzed. The patients were divided into two groups according to the treatment method. Experimental group (n=28) underwent high-voltage long-duration PRF therapy, using ultrasound and X-ray guidance to target the spinal nerve of the affected side, while control group (n=30) was applied with the standard pulsed radiofrequency therapy. Visual analogue scale (VAS), Oswestry disability index (ODI), 36-item short form health survey (SF-36), patient health questionnaire (PHQ-9) before treatment and at 1 week, 1 month, and 6 months after treatment were recorded. Meanwhile, postprocedural complications and adverse reactions were also collected. Results: VAS, ODI, SF-36 and PHQ-9 scores at 1 week, 1 month, and 6 months after treatment were significantly improved in both groups compared with their respective pre-treatment baseline scores (all P<0.01). The differences of VAS, ODI, and PHQ-9 scores between the two groups were not statistically significant at 1 month after treatment (all P>0.05). However, VAS, ODI, and PHQ-9 scores were lower in experiment group than those in control group at 6 months after treatment (all P<0.05). The marked improvement rate and total effective rate at 6 months after treatment in experiment group was 78.6% (22/28) and 92.9% (26/28), respectively, which were higher than that of control group [60.0% (18/30) and 83.3% (25/30), respectively], but the differences were not statistically significant (both P>0.05). No serious complications occurred during the whole period of treatment. Conclusions: Both treatments can effectively relieve the lower limb neuralgia. High-voltage long-term PRF has better efficacy and longer duration than standard PRF.

A setup to measure the temperature-dependent heating power of magnetically heated nanoparticles up to high temperature.

Magnetic heating, namely, the use of heat released by magnetic nanoparticles (MNPs) excited with a high-frequency magnetic field, has so far been mainly used for biological applications. More recently, it has been shown that this heat can be used to catalyze chemical reactions, some of them occurring at temperatures up to 700 °C. The full exploitation of MNP heating properties requires the knowledge of the temperature dependence of their heating power up to high temperatures. Here, a setup to perform such measurements is described based on the use of a pyrometer for high-temperature measurements and on a protocol based on the acquisition of cooling curves, which allows us to take into account calorimeter losses. We demonstrate that the setup permits to perform measurements under a controlled atmosphere on solid state samples up to 550 °C. It should in principle be able to perform measurements up to 900 °C. The method, uncertainties, and possible artifacts are described and analyzed in detail. The influence on losses of putting under vacuum different parts of the calorimeter is measured. To illustrate the setup possibilities, the temperature dependence of heating power is measured on four samples displaying very different behaviors. Their heating power increases or decreases with temperature, displaying temperature sensibilities ranging from -2.5 to +4.4% K-1. This setup is useful to characterize the MNPs for magnetically heated catalysis applications and to produce data that will be used to test models permitting to predict the temperature dependence of MNP heating power.

[Analysis of anxiety, depression and related factors in patients with chronic lumbocrural pain before minimally invasive surgery].

OBJECTIVE: To investigate anxiety and/or depression status of patients with chronic lumbocrural pain, and to further analyze related risk factors of anxiety and/or depression . METHODS: Retrospective analysis of the medical data of patients who suffered from chronic lumbocrural pain caused by lumbar disc herniation and/or lumbar spinal stenosis and received minimally invasive surgery from March 2018 to April 2018. General data (including age, gender, education levels, past history, sleep order and medical insurance), numeric rating scale(NRS), Japanese Orthopedic Association(JOA) back pain scale and hospital anxiety and depression scale(HADS) were collected for analysis. The basic demographic data and clinic data were analyzed, possible related risk factors associated were analyzed by univariate analysis, and multivariate Logistic regression analysis was further used to find the relative independent risk factors and included all the predictive variables with P values less than 0.05 as covariates. RESULTS: A total of 91 patients met the inclusion criteria and finished this study, the mean HADS score for anxiety was 8.1±4.2, 48(52.7%) respondents were screened positive for anxiety, while the rest 43(47.3%) patients had negative anxiety state, the mean HDDS score for depression was 6.9±4.9, 38(41.8%) respondents were screened positive for depression, and the rest 53(58.2%) patients were not depressed, and 56(61.5%) patients experienced anxiety or depression. There were significant difference in sleep disorder, JOA score and leg NRS score between the patients with and without anxiety(P<0.05), and the significant differences were also found in age, sleep disorder and JOA score between the patients with and without depression(P<0.05), Logistic regression analysis further showed that the JOA score and sleep disorder were risk factors for anxiety, and the JOA score was risk factor for depression. CONCLUSION: Patients with chronic lumbocrural pain are often accompanied by anxiety and/or depression before minimally surgery, the low JOA score and sleep disturbance increased the risk of presenting anxiety, and the low JOA score increased the risk of developing depression. It is necessary to evaluate mental status and related risk factors before surgery.

De novo transcriptome characterisation of two auxin-related genes associated with plant growth habit in Astragalus adsurgens Pall.

Astragalus adsurgens Pall., a perennial legume native to China, is commonly used as a forage crop. And it has great value for sustainable development of grasslands in arid and semi arid regions. However, to date, little is known regarding the A. adsurgens genome, and no studies have determined whether it would be possible to improve the germplasm of A. adsurgens through genetic modification. In this study, we used an RNA-seq protocol to generate a de novo transcriptome including 151,516 unigenes of A. adsurgens. We compared the transcriptomes of A. adsurgens having different growth habits (prostrate/erect) and identified 14,133 single nucleotide polymorphism sites (SNP) in 8,139 unigenes. Differential expression gene (DEG) analysis suggested that 10,982 unigenes were up-regulated in the prostrate plant relative to the erect plant, while 10,607 unigenes were down-regulated. Of the 21,589 DEG, Unigene72782_All (LAX4) and CL12494.Contig3_All (TIR1), an auxin transporter gene and an auxin transport inhibitor gene, respectively, were predicted to influence the growth habit of A. adsurgens, which were verified by qRT-PCR in these phenotypes. These results suggest that auxin transport was more active in the prostrate plant than in the erect plant, resulting in asymmetric distribution of auxin that affects the growth habit of A. adsurgens. Overall, this study may provide a basis for future research on key genes in A. adsurgens and may deepen our understanding of the molecular mechanisms regulating plant growth habit.

Circulating Tumor DNA Analysis for Detection of Minimal Residual Disease After Chemoradiotherapy for Localized Esophageal Cancer.

BACKGROUND & AIMS: Biomarkers are needed to risk stratify after chemoradiotherapy for localized esophageal cancer. These could improve identification of patients at risk for cancer progression and selection of additional therapy. METHODS: We performed deep sequencing (CAncer Personalized Profiling by deep Sequencing, [CAPP-Seq]) analyses of plasma cell-free DNA collected from 45 patients before and after chemoradiotherapy for esophageal cancer, as well as DNA from leukocytes and fixed esophageal tumor biopsy samples collected during esophagogastroduodenoscopy. Patients were treated from May 2010 through October 2015; 23 patients subsequently underwent esophagectomy, and 22 did not undergo surgery. We also sequenced DNA from blood samples from 40 healthy control individuals. We analyzed 802 regions of 607 genes for single-nucleotide variants previously associated with esophageal adenocarcinoma or squamous cell carcinoma. Patients underwent imaging analyses 6-8 weeks after chemoradiotherapy and were followed for 5 years. Our primary aim was to determine whether detection of circulating tumor DNA (ctDNA) after chemoradiotherapy is associated with risk of tumor progression (growth of local, regional, or distant tumors, detected by imaging or biopsy). RESULTS: The median proportion of tumor-derived DNA in total cell-free DNA before treatment was 0.07%, indicating that ultrasensitive assays are needed for quantification and analysis of ctDNA from localized esophageal tumors. Detection of ctDNA after chemoradiotherapy was associated with tumor progression (hazard ratio, 18.7; P < .0001), formation of distant metastases (hazard ratio, 32.1; P < .0001), and shorter disease-specific survival times (hazard ratio, 23.1; P < .0001). A higher proportion of patients with tumor progression had new mutations detected in plasma samples collected after chemoradiotherapy than patients without progression (P = .03). Detection of ctDNA after chemoradiotherapy preceded radiographic evidence of tumor progression by an average of 2.8 months. Among patients who received chemoradiotherapy without surgery, combined ctDNA and metabolic imaging analysis predicted progression in 100% of patients with tumor progression, compared with 71% for only ctDNA detection and 57% for only metabolic imaging analysis (P < .001 for comparison of either technique to combined analysis). CONCLUSIONS: In an analysis of cell-free DNA in blood samples from patients who underwent chemoradiotherapy for esophageal cancer, detection of ctDNA was associated with tumor progression, metastasis, and disease-specific survival. Analysis of ctDNA might be used to identify patients at highest risk for tumor progression.

Managing uncertain recovery for patients nearing the end of life in hospital: a mixed-methods feasibility cluster randomised controlled trial of the AMBER care bundle.

BACKGROUND: The AMBER (Assessment, Management, Best Practice, Engagement, Recovery Uncertain) care bundle is a complex intervention used in UK hospitals to support patients with uncertain recovery. However, it has yet to be evaluated in a randomised controlled trial (RCT) to identify potential benefits or harms. The aim of this trial was to investigate the feasibility of a cluster RCT of the AMBER care bundle. METHODS: This is a prospective mixed-methods feasibility cluster RCT. Quantitative data collected from patients (or proxies if patients lack capacity) were used (i) to examine recruitment, retention and follow-up rates; (ii) to test data collection tools for the trial and determine their optimum timing; (iii) to test methods to identify the use of financial resources; and (iv) to explore the acceptability of study procedures for health professionals and patients. Descriptive statistical analyses and thematic analysis used the framework approach. RESULTS: In total, 894 patients were screened, of whom 220 were eligible and 19 of those eligible (8.6%) declined to participate. Recruitment to the control arm was challenging. Of the 728 patients screened for that arm, 647 (88.9%) were excluded. Overall, 65 patients were recruited (81.3% of the recruitment target of 80). Overall, many were elderly (≥80 years, 46.2%, n = 30, mean = 77.8 years, standard deviation [SD] = 12.3 years). Over half (53.8%) had a non-cancer diagnosis, with a mean of 2.3 co-morbidities; 24.6% patients (n = 16) died during their hospital stay and 35.4% (n = 23) within 100 days of discharge. In both trial arms, baseline IPOS subscale scores identified moderate patient anxiety (control: mean 13.3, SD 4.8; intervention: mean 13.3, SD 5.1), and howRwe identified a good care experience (control: mean 13.1, SD 2.5; intervention: mean 11.5, SD 2.1). Collecting quantitative service use and quality of life data was feasible. No patient participants regarded study involvement negatively. Focus groups with health professionals identified concerns regarding (i) the subjectivity of the intervention's eligibility criteria, (ii) the need to prognosticate to identify potential patients and (iii) consent procedures and the length of the questionnaire. CONCLUSIONS: A full trial of the AMBER care bundle is technically feasible but impractical due to fundamental issues in operationalising the intervention's eligibility criteria, which prevents optimal recruitment. Since this complex intervention continues to be used in clinical care and advocated in policy, alternative research approaches must be considered and tested. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) Register, ISRCTN36040085 .

Genomic and epidemiological monitoring of yellow fever virus transmission potential.

The yellow fever virus (YFV) epidemic in Brazil is the largest in decades. The recent discovery of YFV in Brazilian Aedes species mosquitos highlights a need to monitor the risk of reestablishment of urban YFV transmission in the Americas. We use a suite of epidemiological, spatial, and genomic approaches to characterize YFV transmission. We show that the age and sex distribution of human cases is characteristic of sylvatic transmission. Analysis of YFV cases combined with genomes generated locally reveals an early phase of sylvatic YFV transmission and spatial expansion toward previously YFV-free areas, followed by a rise in viral spillover to humans in late 2016. Our results establish a framework for monitoring YFV transmission in real time that will contribute to a global strategy to eliminate future YFV epidemics.

Ambipolar transport and magneto-resistance crossover in a Mott insulator, Sr2IrO4.

Electric field effect (EFE) controlled magnetoelectric transport in thin films of undoped and La-doped Sr2IrO4 (SIO) is investigated using ionic liquid gating. The temperature dependent resistance measurements exhibit insulating behavior in chemically and EFE doped samples with the band filling up to 10%. The ambipolar transport across the Mott gap is demonstrated by EFE tuning of the channel resistance and chemical doping. We observe a crossover from high temperature negative to low temperature positive magnetoresistance around ∼80-90 K, irrespective of the filling. This temperature and magnetic field dependent crossover is discussed in the light of conduction mechanisms of SIO, especially variable range hopping (VRH), and its relevance to the insulating ground state of SIO.

[Thought on the techniques of totally thoracoscopic cardiac surgery].

Minimally invasive surgery has become the guiding principle of the entire surgical treatment. In last 16 years, totally thoracoscopic cardiac surgery (TTCS) has developed rapidly, and achieved good results. However, there are obvious differences between the basic surgical techniques of TTCS and of conventional cardiac surgery. At present, there is still lack of standard and in sufficient evidence in the surgical techniques of TTCS. It requires professional and standardized training and evidence-based research on TTCS, including indication selection and procedure standardization, to improve the therapy level of TTCS further.

Comparative sequence and expression analysis of tapetum specific male sterility related genes in Medicago truncatula.

Heterosis, or enhancement through outbreeding, is one of the most promising approaches for increasing crop yield. Male sterility (MS), which promotes heterosis, has been widely applied in hybrid crop production. Medicago truncatula is a model legume species and is closely related to M. sativa, an important legume forage plant. Although the molecular mechanisms of MS in M. truncatula and M. sativa remain unclear, several studies of MS have been conducted in Arabidopsis thaliana. Previous research has shown that MS is associated with the destruction of tapetal cell layers. Disruption of tapetum developmental processes may result in pollen abortion. In an effort to identify genes useful for breeding in M. sativa, we identified MS related genes in M. truncatula using BLAST and homology to A. thaliana genes. In this study, we identified 63 tapetum specific male sterility (TSMS) related genes. The length of TSMS genes varied from 225 to 3747 bp. We identified 15 conserved domains and 8 cis-elements associated with TSMS related genes. Analysis of the phylogenetic relationships among these genes allowed them to be classified into three groups, MtTsms A, MtTsms B, and MtTsms C. Expression analyses revealed that these genes may be involved in developmental processes and response to abiotic stress.

Evaluation of chest CT scan in low-weight children with ultralow tube voltage (70 kVp) combined with Flash scan technique.

OBJECTIVE: To assess radiation dose and image quality of chest CT examinations in low-weight children acquired at ultralow tube voltage (70 kVp) combined with Flash scan technique. MATERIALS AND METHODS: 30 consecutive paediatric patients (weight <20 kg) required non-contrast chest CT at 70 kVp with Flash scan mode (Group A). 30 patients for paediatric standard 80-kVp protocols with conventional spiral mode (Group B) were selected from the picture archiving and communication system. For each examination, the volume CT dose index (CTDIvol) and dose-length product (DLP), and the effective dose (adapted as 16-cm phantom) (ED16cm) were estimated. The image noise, signal-to-noise ratio (SNR), overall subjective image quality and respiratory motion artefacts were evaluated. RESULTS: For radiation dose, CTDIvol (mGy), DLP (mGy cm) and ED16cm (mSv) of Group A were significantly lower than those of Group B [CTDIvol: 0.48 ± 0.003 mGy (Group A) vs 0.80 ± 0.005 mGy (Group B); p<0.001 DLP: 10.23 ± 1.35 mGy cm (Group A) vs 15.6 ± 2.02 mGy cm (Group B); p<0.001 ED16cm: 0.61 ± 0.91 mSv (Group A) vs 0.89 ± 0.13 mSv (Group B); p<0.001]. The mean image noise with Group A increased 28.5% (p = 0.002), and the mean SNR decreased 14.8% compared with Group B (p = 0.193). There was no statistical difference in overall subjective image quality grades, and Group A had significantly lower respiratory motion artefact grades than Group B (p < 0.001). CONCLUSION: Ultralow tube voltage (70 kVp) combined with the Flash scan technique of the chest can obtain images with clinically acceptable image noise and minimum respiratory motion artefacts in low-weight children, whilst reducing radiation dose significantly. ADVANCES IN KNOWLEDGE: The feasibility of chest CT scan in low-weight children with ultralow tube voltage (70 kVp) combined with Flash scan technique has firstly been evaluated in our study.

Brain mechanisms of pain relief by transcutaneous electrical nerve stimulation: A functional magnetic resonance imaging study.

BACKGROUND: Although the exact mechanism of TENS pain relief is unknown, it is believed that TENS impulses interrupt nociceptive signals at the dorsal horn of the spinal cord. AIMS: To evaluate the hypotheses that during pain caused by noxious stimuli, brain responses, temporal summation and brain functional connectivity are modulated by TENS, and that mechanisms of pain relief by TENS differ between men and women. METHODS: During fMRI scanning, the same noxious stimuli were delivered to each participant in pain-only and pain+TENS conditions. In the pain-only condition, noxious stimuli were presented without TENS. In the pain+TENS condition, participants received noxious stimuli and TENS concurrently. Participants were initially presented with TENS at an intensity that was just below that causing discomfort. TENS intensity was presented in a step-wise fashion to prevent temporal summation from repetitive noxious stimuli. RESULTS: Pain and unpleasantness ratings were significantly higher in the pain-only than the pain+TENS condition. With non-painful TENS, primary and secondary somatosensory and parietal cortices were activated, and temporal summation from repetitive noxious stimuli was prevented. Periaqueductal gray (PAG) and lateral prefrontal cortex functional connectivity was increased by TENS, and modulated by testosterone and cortisol. Women reported greater pain during TENS than men, and showed greater activation in the temporoparietal junction cortex and increased PAG functional connectivity with the orbitofrontal cortex. CONCLUSION: TENS led to pain reduction, probably due to activation of the descending pain-inhibitory pathway, indicating that this TENS method may be applied in clinical practice.