The tripartite motif (TRIM) family of E3 ubiquitin ligases is well known for its roles in antiviral restriction and innate immunity regulation, in addition to many other cellular pathways. In ...particular, TRIM25-mediated ubiquitination affects both carcinogenesis and antiviral response. While individual substrates have been identified for TRIM25, it remains unclear how it regulates diverse processes. Here we characterized a mutation, R54P, critical for TRIM25 catalytic activity, which we successfully utilized to "trap" substrates. We demonstrated that TRIM25 targets proteins implicated in stress granule formation (G3BP1/2), nonsense-mediated mRNA decay (UPF1), nucleoside synthesis (NME1), and mRNA translation and stability (PABPC4). The R54P mutation abolishes TRIM25 inhibition of alphaviruses independently of the host interferon response, suggesting that this antiviral effect is a direct consequence of ubiquitination. Consistent with that, we observed diminished antiviral activity upon knockdown of several TRIM25-R54P specific interactors including NME1 and PABPC4. Our findings highlight that multiple substrates mediate the cellular and antiviral activities of TRIM25, illustrating the multi-faceted role of this ubiquitination network in modulating diverse biological processes.
Background
The rampant spread of the novel coronavirus disease (COVID‐19) has assumed pandemic proportions across the world. Attempts to contain its spread have entailed varying early screening and ...triage strategies implemented in different countries and regions.
Aim
To share the experience of scientific and standardized management of fever clinics in China, which provide the first effective checkpoint for the prevention and control of COVID‐19.
Introduction
A fever clinic was established at our hospital in Tianjin, China, for initially identifying suspected cases of COVID‐19 and controlling the spread of the disease.
Methods
The management system covered the following aspects: spatial layout; partitioning of functional zones; a work management system and associated processes; management of personnel, materials and equipment; and patient education.
Results
Within two months of introducing these measures, there was a comprehensive reduction in the number of new COVID‐19 cases in Tianjin, and zero infections occurred among medical staff at the fever clinic.
Discussion
The fever clinic plays an important role in the early detection, isolation and referral of patients presenting with fevers of unknown origin. Broad screening criteria, an adequate warning mechanism, manpower reserves and staff training at the clinic are essential for the early management of epidemics.
Conclusion
The spread of COVID‐19 has been effectively curbed through the establishment of the fever clinic, which merits widespread promotion and application.
Implications for nursing and health policies
Health managers should be made aware of the important role of fever clinics in the early detection, isolation and referral of patients, and in the treatment of infectious diseases to prevent and control their spread. In the early stage of an epidemic, fever clinics should be established in key areas with concentrated clusters of cases. Simultaneously, the health and safety of health professionals require attention.
Data from clinical trials of human papillomavirus (HPV) vaccines showed that women naïve (negative for both type-specific antibodies and DNA) to vaccine types would derive benefit from vaccination; ...therefore, an understanding of the proportion of naïve women in different age groups is important for developing HPV vaccination strategies.
From November 2012 to April 2013, a total of 7372 healthy women aged 18–45 years were recruited in five provinces in China. Cervical specimens and serum samples were collected for each woman at entry. Cervical specimens were first tested by the HPV DNA enzyme immunoassay method; if positive, the specimens were then tested by reverse hybridization line probe assay and HPV-16 and HPV-18 specific polymerase chain reactions. Neutralizing antibodies against HPV-16 or HPV-18 were tested with a pseudovirion-based neutralization assay.
The overall prevalence of high-risk HPV DNA was 14.8% (1088/7367, 95% CI 14.0–15.6), and the seroprevalence of neutralizing antibodies against HPV-16 and HPV-18 was 12.6% (925/7367) and 4.9% (364/7367), respectively. In younger women (18–26 years) and middle-aged women (27–45 years), 83.8% (3116/3719) and 81.4% (2968/3648) were naïve to both HPV-16 and HPV-18 (both neutralizing antibodies and DNA were negative), respectively. In addition, 98.5% (3664/3719) and 98.0% (3575/3648) of the younger or middle-aged women were naïve to at least one HPV type (HPV-16 or HPV-18).
This study revealed that the majority of Chinese women aged 18–26 years and 27–45 years were naïve to both HPV-16 and HPV-18 and would thus derive full benefit from bivalent HPV vaccination.
Abstract Ketamine exerts fast acting, robust, and lasting antidepressant effects in a sub-anesthetic dose, however, the underlying mechanisms are still not fully elucidated. Recent studies have ...suggested that ketamine's antidepressant effects are probably attributed to the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The present study aimed to observe the effects of AMPA receptor modulators on mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF) expression during the procedure of ketamine exerting antidepressant effects. Therefore, we pretreated rats with NBQX, an AMPA receptor antagonist, or CX546, an AMPA receptor agonist, and subsequently observed the immobility time during the forced swimming test (FST) and the hippocampal and prefrontal cortical levels of mTOR and BDNF. The results showed ketamine decreased the immobility time of rats during the FST and increased the hippocampal and prefrontal cortical mTOR and BDNF. NBQX pretreatment significantly increased the immobility time and decreased the levels of mTOR and BDNF when compared with vehicle 1 (DMSO) pretreatment. CX546 pretreatment significantly decreased the immobility time and increased the levels of mTOR and BDNF when compared with vehicle 2 (DMSO + ethanol) pretreatment. Our results suggest ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex.
With sufficient high cooling rates, a variety of liquids, including metallic melts, will cross a glass transition temperature and solidify into glass accompanying a marked increase of the shear ...viscosity in approximately 17 orders of magnitude. Because of the intricate atomic structure and dynamic behaviours of liquid, it is yet difficult to capture the underlying structural mechanism responsible for the marked slowing down during glass transition, which impedes deep understanding of the formation and nature of glasses. Here, we report that a universal structural indicator, the average degree of five-fold local symmetry, can well describe the slowdown dynamics during glass transition. A straightforward relationship between structural parameter and viscosity (or α-relaxation time) is introduced to connect the dynamic arrest and the underlying structural evolution. This finding would be helpful in understanding the long-standing challenges of glass transition mechanism in the structural perspective.
Antibacterial adhesives have favorable prospects to inhibit biofilms and secondary caries. The objectives of this study were to investigate the antibacterial effect of dental adhesives containing ...dimethylaminododecyl methacrylate (DMADDM) on different bacteria in controlled multispecies biofilms and its regulating effect on development of biofilm for the first time. Antibacterial material was synthesized, and Streptococcus mutans, Streptococcus gordonii, and Streptococcus sanguinis were chosen to form multispecies biofilms. Lactic acid assay and pH measurement were conducted to study the acid production of controlled multispecies biofilms. Anthrone method and exopolysaccharide (EPS):bacteria volume ratio measured by confocal laser scanning microscopy were performed to determine the EPS production of biofilms. The colony-forming unit counts, scanning electron microscope imaging, and dead:live volume ratio decided by confocal laser scanning microscopy were used to study the biomass change of controlled multispecies biofilms. The TaqMan real-time polymerase chain reaction and fluorescent in situ hybridization imaging were used to study the proportion change in multispecies biofilms of different groups. The results showed that DMADDM-containing adhesive groups slowed the pH drop and decreased the lactic acid production noticeably, especially lactic acid production in the 5% DMADDM group, which decreased 10- to 30-fold compared with control group (P < 0.05). EPS was reduced significantly in 5% DMADDM group (P < 0.05). The DMADDM groups reduced the colony-forming unit counts significantly (P < 0.05) and had higher dead:live volume ratio in biofilms compared with control group (P < 0.05). The proportion of S. mutans decreased steadily in DMADDM-containing groups and continually increased in control group, and the biofilm had a more healthy development tendency after the regulation of DMADDM. In conclusion, the adhesives containing DMADDM had remarkable antimicrobial properties to serve as “bioactive” adhesive materials and revealed its potential value for antibiofilm and anticaries clinical applications.
The prediction of the glass-forming ability (GFA) by varying the composition of alloys is a challenging problem in glass physics, as well as a problem for industry, with enormous financial ...ramifications. Although different empirical guides for the prediction of GFA were established over decades, a comprehensive model or approach that is able to deal with as many variables as possible simultaneously for efficiently predicting good glass formers is still highly desirable. Here, by applying the support vector classification method, we develop models for predicting the GFA of binary metallic alloys from random compositions. The effect of different input descriptors on GFA were evaluated, and the best prediction model was selected, which shows that the information related to liquidus temperatures plays a key role in the GFA of alloys. On the basis of this model, good glass formers can be predicted with high efficiency. The prediction efficiency can be further enhanced by improving larger database and refined input descriptor selection. Our findings suggest that machine learning is very powerful and efficient and has great potential for discovering new metallic glasses with good GFA.
The geometry which is the topic of this book is that determined by a map of one space N onto another, M, mapping a diffusion process, or operator, on N to one on M. Filtering theory is the science of ...obtaining or estimating information about a system from partial and possibly flawed observations of it. The system itself may be random, and the flaws in the observations can be caused by additional noise. In this volume the randomness and noises will be of Gaussian white noise type so that the system can be modelled by a diffusion process, that is it evolves continuously in time in a Markovian way, the future evolution depending only on the present situation. This is the standard situation of systems governed by Ito type stochastic differential equations. The state space will be the smooth manifold, N, possibly infinite dimensional, and the 'observations' will be obtained by a smooth map onto another manifold, N, say. We emphasise that the geometry is important even when both manifolds are Euclidean spaces. This can also be viewed from a purely partial differential equations viewpoint as one smooth second order elliptic partial differential operator lying above another, both with no zero order term. We consider the geometry of this situation with special emphasis on situations of geometric, stochastic analytic, or filtering interest. The most well studied case is of one Brownian motion being mapped to another with a consequent skew product decomposition (or equivalently the case of Riemannian submersions). This sort of decomposition is generalised and a key to the rest of the book. It is used to study in particular, classical filtering, (semi-)connections determined by stochastic flows, and generalised Weitzenbock formulae.
To investigate the value of a radiomics nomogram integrating intratumoural and peritumoural features in predicting lymph node metastasis and overall survival (OS) in patients with clinical stage IA ...non-small-cell lung cancer (NSCLC).
This study retrospectively enrolled 199 patients (training cohort: 71 patients from Affiliated Tumour Hospital of Nantong University; internal validation cohort: 46 patients from Affiliated Tumour Hospital of Nantong University; external validation cohort: 82 patients from the public database). CT radiomics models were constructed based on four volumes of interest: gross tumour volume (GTV), gross and 3 mm peritumoural volume (GPTV3), gross and 6 mm peritumoural volume (GPTV6), and gross and 9 mm peritumoural volume (GPTV9). The optimal radiomics signature was further combined with independent clinical predictors to develop a nomogram. Univariable and multivariable Cox regression analysis were applied to determine the relationship between factors and OS.
GPTV6 radiomics yielded better performance than GTV, GPTV3, and, GPTV9 radiomics in the training (area under the curve AUC, 0.81), internal validation (AUC, 0.79), and external validation cohorts (AUC, 0.71), respectively. The nomogram integrating GPTV6 radiomics and spiculation improved predictive ability, with AUCs of 0.85, 0.80, and 0.74 in three cohorts, respectively. Pathological lymph node metastasis, nomogram-predicted lymph node metastasis, and pleural indentation were independent risk predictors of OS (p<0.05).
The nomogram integrating GPTV6 radiomics features and independent clinical predictors performed well in predicting lymph node metastasis and prognosis in patients with clinical stage IA NSCLC.
•Intratumoral and peritumoral 6 mm radiomics features showed good performance.•The nomogram could predict lymph node metastasis and prognosis.•The nomogram outperformed the radiomics model and clinical model.
Background
Regional anaesthesia may have advantages in preserving immune function. Tumor‐infiltrating lymphocytes (TILs) are considered indicators of immune response in the tumor microenvironment and ...used as a prognostic marker in patients after cancer surgery. This study investigated the effects of combined epidural anaesthesia on the number of TILs in patients undergoing surgery for lung adenocarcinoma.
Methods
Patients undergoing radical resection for primary lung cancer were randomized to receive either combined epidural‐general anaesthesia (Epi‐GA) or general anaesthesia (GA) in an ongoing randomized controlled trial (ChiCTR‐TRC‐14004136). Excised adenocarcinoma specimens from patients enrolled between 1 June 2015 and 30 November 2015 were selected for immunohistochemical staining of CD8 and FOXP3 molecules. The numbers of positive lymphocytes were counted and expressed as the number of cells per mm2 tumor area.
Results
One hundred and twenty‐eight patients were recruited and randomized; 64 patients were included in immunohistochemistry analysis (37 received Epi‐GA vs. 27 received GA). The number of CD8+ T cells was higher in the Epi‐GA group than in the GA group (median interquartile range: 292.8 198.0–418.3 vs. 204.7 131.1–305.8, P = 0.036); whereas the number of FOXP3+ T cells was less in the Epi‐GA group than in the GA group (37.6 14.7–92.3 vs. 99.8 68.9–168.3, P < 0.001).
Conclusions
For patients undergoing surgery for lung adenocarcinoma under general anesthesia, use of epidural anaesthesia increased CD8+ T cells infiltration but decreased FOXP3+ T cells accumulation in tumor tissues. Epidural anaesthesia may affect TILs in a manner that preserves immune function.
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