Mathematical modelling and release thresholds of transgenic sterile mosquitoes.

We formulate simple differential equation models to study the impact of releases of transgenic sterile mosquitoes carrying a dominant lethal on mosquito control based on the modified sterile insects technique. The early acting bisex, late acting bisex, early acting female-killing, and late acting female-killing lethality strategies are all considered. We determine release thresholds of the transgenic sterile mosquitoes, respectively, for these models by investigating the existence of positive equilibria and their stability. We compare the model dynamics, in particular, the thresholds of the models numerically. The late acting lethality strategies are generally more effective than their corresponding early acting lethality strategies, but the comparison between the late acting bisex and early acting female-killing lethality strategies depends on different parameter settings.

Global asymptotic stability in a pseudorabies virus model with age structure.

Pseudorabies is a highly contagious disease caused by pseudorabies virus (PRV) or suid herpesvirus 1 (SuHV1), causing significant economic losses to the swine industry in countries where the disease exists. In this paper, we formulate an age structure model of pseudorabies virus that takes into account disease-related mortality and vertical transmission. We find a threshold to determine the stability and existence of the disease. We show that there is always a globally asymptotically stable boundary equilibrium if and only if R02<1+θ, which means that the disease always exists in piglets and will die out in adult pigs. When R02>1+θ, the boundary equilibrium is unstable and there exists a unique disease-endemic equilibrium, which is globally asymptotically stable. We give detailed proofs of our theoretical results and numerical examples. Brief concluding remarks are also provided.

Research progress on the mechanism of chronic neuropathic pain.

Chronic neuropathic pain (CNP) refers to pain that lasts for more than three months due to a disease or an injury to the somatosensory nervous system. The incidence of CNP has been increasing in the world, causing it to become a global concern and patients often experience spontaneous pain, hyperalgesia, abnormal pain or even abnormal sensation as some of its main symptoms. In addition to serious pain and poor physical health, CNP also negatively affects patients' mental health, thus impacting the overall quality of their lives. The pathogenesis of CNP is not clear, but some studies have proved that central sensitization, peripheral sensitization, neuroinflammation, dysfunction in descending nociceptive modulatory systems, oxidative stress reaction, activation of glial cells and psychological factors play an important role in the occurrence and development of CNP. In this context, this article summarizes the current research progress on the mechanism of CNP to provide a basis for further research in preventing and treating the disease.

A Mosquito Population Suppression Model by Releasing Wolbachia-Infected Males.

Due to the role of cytoplasmic incompatibility (CI), releasing Wolbachia-infected male mosquitoes into the wild becomes a very promising strategy to suppress the wild mosquito population. When developing a mosquito suppression strategy, our main concerns are how often, and in what amount, should Wolbachia-infected mosquitoes be released under different CI intensity conditions, so that the suppression is most effective and cost efficient. In this paper, we propose a mosquito population suppression model that incorporates suppression and self-recovery under different CI intensity conditions. We adopt the new modeling idea that only sexually active Wolbachia-infected male mosquitoes are considered in the model and assume the releases of Wolbachia-infected male mosquitoes are impulsive and periodic with period T. We particularly study the case where the release period is greater than the sexual lifespan of the Wolbachia-infected male mosquitoes. We define the CI intensity threshold, mosquito release thresholds, and the release period threshold to characterize the model dynamics. The global and local asymptotic stability of the origin and the existence and stability of T-periodic solutions are investigated. Our findings provide useful guidance in designing practical release strategies to control wild mosquitoes.

Discrete-time models for interactive wild and sterile mosquitoes with general time steps.

Different from the discrete-time population models based on evolution of generations or life cycles, we formulate discrete-time homogeneous and stage-structured models with time steps in more general settings such that survivals are included at each time step. We assume that sterile mosquitoes are released and their number in the field is kept at a constant level. We study the interactive dynamics of wild and sterile mosquitoes where only sexually active sterile mosquitoes are considered. We determine threshold values of releases and investigate the interactive dynamics for both homogeneous and stage-structured populations. Numerical examples are provided to confirm and demonstrate the obtained theoretical results.

A delay suppression model with sterile mosquitoes release period equal to wild larvae maturation period.

Based on the idea that only sexually active sterile mosquitoes are included in the modeling process, we study the dynamics of the interactive wild and sterile mosquito model with time delay, which consists of three sub-equations. Due to the fact that the maturation period of sterile mosquitoes bred in the lab or mosquito factories is almost the same time period of wild adult mosquitoes matured from larvae, we particularly assume that the waiting period for two consecutive releases of sterile mosquitoes equals the maturation period of wild mosquitoes, as a new practical sterile mosquito release strategy. We first ingeniously solve the delay model with the initial functions that are solutions of the corresponding equation without delay and we call them "good" solutions. Using these "good" solutions, we then surprisedly obtain sufficient and necessary conditions for the trivial solution and a unique periodic solution of the delay model to be globally asymptotically stable, respectively. We provide a numerical example to demonstrate the model dynamics and brief discussions of our findings as well.

Approximating gene transcription dynamics using steady-state formulas.

Understanding how genes in a single cell respond to dynamically changing signals has been a central question in stochastic gene transcription research. Recent studies have generated massive steady-state or snapshot mRNA distribution data of individual cells, and inferred a large spectrum of kinetic transcription parameters under varying conditions. However, there have been few algorithms to convert these static data into the temporal variation of kinetic rates. Real-time imaging has been developed to monitor stochastic transcription processes at the single-cell level, but the immense technicality has prevented its application to most endogenous loci in mammalian cells. In this article, we introduced a stochastic gene transcription model with variable kinetic rates induced by unstable cellular conditions. We approximated the transcription dynamics using easily obtained steady-state formulas in the model. We tested the approximation against experimental data in both prokaryotic and eukaryotic cells and further solidified the conditions that guarantee the robustness of the method. The method can be easily implemented to provide convenient tools for quantifying dynamic kinetics and mechanisms underlying the widespread static transcription data, and may shed a light on circumventing the limitation of current bursting data on transcriptional real-time imaging.

Prophylactic Norepinephrine Infusion Reduces Postoperative Complications and Hospitalization Time in Elderly Patients Undergoing Posterior Lumbar Spinal Fusion.

This single-center prospective randomized controlled trial explores the effect of prophylactic norepinephrine infusion on the incidence of complications and hospitalization time in elderly patients (60-85 years old) undergoing posterior lumbar spinal fusion. In total, 129 elderly patients were randomized into two groups: a group that received norepinephrine during general anesthesia and a control group not receiving norepinephrine. The primary outcomes were in-hospital complications and 90-day postoperative complications and hospitalization time. The results show that in-hospital complications occurred in 24 of 60 patients (40%) in the control group versus 11 of 60 patients (18.3%) in the norepinephrine group (RR, 2.182; 95% CI, 1.177-4.045; P = 0.015). Cardiac events occurred significantly more frequently in the control than in the norepinephrine group. Total number of patients experiencing complications within 90 days postoperatively was lower in the norepinephrine (11 of 60; 18.3%) than in the control group (26 of 60; 43.3%; RR, 2.364; 95% CI, 1.288-4.339; P = 0.005). The median length of hospital stay was 17 days (11-27) in the control group and 15 days (10- 23) in the norepinephrine group (P = 0.01). The secondary outcomes were serum levels of syndecan-1, hyaluronic acid, heparan sulfate, and brain natriuretic peptide. Logistic regression analysis is used to describe the relationship between selected independent variables and in-hospital complications. Intraoperative total fluid, crystalloid, and colloid volumes were significantly higher in the control than in the norepinephrine group. The patients in the norepinephrine group had a higher MAP but a lower heart rate than those in the control group after the induction of anesthesia and intraoperatively. Syndecan-1, hyaluronic acid, and heparan sulfate serum levels showed a different course in the two groups. In conclusion, prophylactic norepinephrine infusion during posterior lumbar spinal fusion is preferable for elderly patients undergoing lumbar spinal fusion under general anesthesia. It can reduce postoperative complications and hospitalization time by reducing the injury to the vascular endothelium. This trial is registered with Clinical Trial Registration http://www.chictr.org.cn/showproj.aspx?proj=33660, identifier ChiCTR-1900021309.

Expert consensus of Chinese Association for the Study of Pain on the application of ozone therapy in pain medicine.

This consensus was compiled by first-line clinical experts in the field of pain medicine and was organized by the Chinese Association for the Study of Pain. To reach this consensus, we consulted a wide range of opinions and conducted in-depth discussions on the mechanism, indications, contraindications, operational specifications and adverse reactions of ozone iatrotechnique in the treatment of pain disorders. We also referred to related previous preclinical and clinical studies published in recent years worldwide. The purpose of this consensus is to standardize the rational application of ozone iatrotechnique in pain treatment, to improve its efficacy and safety and to reduce and prevent adverse reactions and complications in this process.

Effect of intraoperative blood transfusion on Treg and FOXP3 in patients with digestive tract malignancies and different ABO blood types.

BACKGROUND: Blood transfusion can cause immunosuppression and lead to worse outcomes in patients with digestive tract malignancies; however, the specific mechanism behind this is not completely understood. One theory is that increased numbers of regulatory CD3+CD4+CD25+FOXP3+ T cells (Tregs) and forkhead box protein-3 mRNA (FOXP3) expression in the blood after transfusion contribute to these outcomes. The effect of blood transfusion on immune function in patients with different ABO blood types is variable. This study investigates the effect of intraoperative blood transfusion on the number of Tregs and the expression of FOXP3 in the blood of patients with different ABO blood types and digestive tract malignancies. METHODS: Patients with digestive tract malignancies who underwent radical resection and received intraoperative blood transfusion were divided into four groups according to their blood types:blood group A, blood group B, blood group O and blood group AB (n = 20 for each group). Blood was collected from all patients before surgery, immediately after transfusion, 1 day after transfusion, and 5 days after transfusion. The number of Tregs was measured by flow cytometry. The expression of FOXP3 was detected by real time reverse transcription polymerase chain reaction (RT-PCR). RESULTS: There was no significant difference in the number of Tregs or expression of FOXP3 mRNA among patients with different blood types before surgery. However, the number of Tregs and the expression of FOXP3 increased after blood transfusion in all blood type groups. This increase was especially evident and statistically significant on the first day after blood transfusion when compared with measures obtained before the surgery. Measures returned to the preoperative level five days after surgery. There were significant differences in the increase of Tregs and expression of FOXP3 among patients with different blood types. The greatest increase was seen in patients with blood group B and the least in blood group A. CONCLUSIONS: Intraoperative blood transfusion can lead to an increase in blood Tregs and FOXP3 expression in patients with digestive tract malignancies. Increases were greatest on the first day after surgery and differed among patients with different blood types. Increases were greatest in blood type B and least in blood type A.

Mosquito Control Based on Pesticides and Endosymbiotic Bacterium Wolbachia.

Mosquito-borne diseases, such as dengue fever and Zika, have posed a serious threat to human health around the world. Controlling vector mosquitoes is an effective method to prevent these diseases. Spraying pesticides has been the main approach of reducing mosquito population, but it is not a sustainable solution due to the growing insecticide resistance. One promising complementary method is the release of Wolbachia-infected mosquitoes into wild mosquito populations, which has been proven to be a novel and environment-friendly way for mosquito control. In this paper, we incorporate consideration of releasing infected sterile mosquitoes and spraying pesticides to aim to reduce wild mosquito populations based on the population replacement model. We present the estimations for the number of wild mosquitoes or infection density in a normal environment and then discuss how to offset the effect of the heatwave, which can cause infected mosquitoes to lose Wolbachia infection. Finally, we give the waiting time to suppress wild mosquito population to a given threshold size by numerical simulations.

Mechanism of Mongolian Medicine Eerdun Wurile in Improving Postoperative Cognitive Dysfunction Through Activation of the PI3K Signaling Pathway.

OBJECTIVE: To study the effect of Eerdun Wurile (EW), a traditional Mongolian medicine, on the cognitive function of rats by activating the IRS-PI3K-AKT-GLUT4 pathway in an animal model of postoperative cognitive dysfunction (POCD). METHODS: Fifty clean-grade adults Sprague Dawley (SD) male rats were assigned to one of five groups: (1) a control group with no anesthesia (Group C), (2) a POCD model group with anesthesia only (Group P), (3) POCD group with low-dose EW treated (Group L), (4) a POCD group with high-dose EW treated (Group H), and (5) a POCD model group with dexmedetomidine treated (Group D) for positive control. The study started 7 days after all rats had acclimated to housing. Rats were trained in the Morris Water Maze navigation 5 days before surgery. All rats underwent the same maze for navigation and spatial exploration experiments on the preoperative day 1 and postoperative days 1, 3, 5, and their learning and memory abilities were assessed. At the end of the water maze experiment, rats were sacrificed to obtain hippocampal tissue. The mRNA levels of IRS-2, PI3K, AKT, and GLUT4 were measured in the hippocampus by real-time PCR, and the expression of IRS-2, PI3K, AKT, and GLUT4 protein in the hippocampus was determined by Western blotting to investigate the potential mechanisms at the molecular level. RESULTS: Compared to control Group C, Group P, L, H, and D showed prolonged escape latency (P < 0.05) and decreased number of times to cross the platform (P < 0.05) at 1, 3 and 5 days after surgery. Compared to Group P, Group L, H, and D showed a decrease in escape latency with an increased number of crossing the platform at all-time points after surgery (P < 0.05). Within individual P, L, H, and D groups, escape latencies decreased (P < 0.05) and the number of times that the platform was crossed increased (P < 0.05) between postoperative days 3 and 5 compared to postoperative 1 day. Compared to Group C, the mRNA expression of IRS-2, PI3K, AKT and GLUT4 in the hippocampus of P, L, H, and D groups were decreased (P < 0.05). Compared to Group P, IRS-2, PI3K, AKT, and GLUT4 in the hippocampus of L, H, and D groups were increased (P < 0.05). Compared with Group D, the expression levels of IRS-2 and AKT in both L and H groups were higher. The expression level of PI3K in Group L was also higher (P < 0.05) vs Group D. The expression of AKT mRNA in Group H was higher than in Group L (P < 0.05). Compared to Group C, the p-IRS-2/IRS-2 ratio in the hippocampus of Group P was higher than that of Group C (P < 0.05). Compared to Group P, the ratios of p-IRS-2/IRS-2 in Group L, Group H, and Group D were lower, and the ratios of the p-PI3K/PI3K, p-AKT/AKT, and p-GLUT4/GLUT4 were higher (P < 0.05). CONCLUSION: Administration of EW showed the effect on the signaling pathway in rats with POCD. The therapeutic effect was better in the low-dose group. This could be related to the insulin downstream signal molecule PI3K and the IRS-PI3K-AKT-GLUT4 signaling pathway.

Effect of positive end-expiratory pressure ventilation on plasma nitric oxide, endothelin-1 and vascular celladhesion molecule-1 levels in patients undergoing uvulopalatopharyngoplasty.

BACKGROUND: During uvulopalatopharyngoplasty (UPPP), cardiovascular adverse events may occur which can be harmful to patients. OBJECTIVE: To evaluate the effect of the protective ventilation strategy on the function of vascular endothelial cells. METHODS: Forty obstructive apnea syndrome (OSA) patients who underwent uvulopalatopharyngoplasty (UPPP) were enrolled. Patients were randomly divided into the control group (group C, PEEP = 0 cm H2O) and PEEP group (group P, PEEP = 5 cm H2O). Each group (n= 20) received intermittent volume controlled ventilation (VCV) with tidal volume 6 ml/kg of the predicted body weight, I:E 1:2, rate titrated for ETCO2 35-45, FiO2 0.7. Blood from the radial artery was sampled for blood gas analysis at four time points: the fifth minute of inhaling pure oxygen (T0), after tracheal intubation (T1), at the end of the operation (T2), and 20 minutes after extubation (T3). Three ml of arterial blood was retained, preserved at -20∘C after serum isolation, and plasma nitric oxide (NO), endothelin-1 (ET-1) and vascular celladhesion molecule-1 (VCAM-1) levels were determined by enzyme linked immunosorbent assay (ELISA). RESULTS: Compared with group C, plasma ET-1 at T3 decreased in group P, and plasma NO levels at T2 and T3 increased (P< 0.05). Compared with samples collected at T0, plasma VCAM-1 levels at T1, T2 and T3 increased in group C, while plasma VCAM-1 levels at T2 and T3 decreased in group P (P< 0.05). Compared with group C, plasma VCAM-1 levels T2 and T3 decreased in group P (P< 0.05). CONCLUSIONS: Positive end-expiratory pressure (PEEP) ventilation has a protective effect on vascular endothelial cell function in patients during UPPP.

Wolbachia infection enhancing and decaying domains in mosquito population based on discrete models.

In this article, we formulate and study a discrete equation model depicting the pattern of Wolbachia infection in a mosquito population. A domain in [Formula: see text] is called a Wolbachia infection enhancing (or decaying) domain if in which the Wolbachia infection frequency of the next generation is always bigger (or smaller) than that of the current generation. We first give a complete analysis of the equivalent Wolbachia infection frequency curves. And then we clearly characterize the Wolbachia infection enhancing domain and decaying domain for all of the parameters, respectively. Finally, some numerical examples are also provided to illustrate our theoretical results.

Dexmedetomidine activates the PI3K/Akt pathway to inhibit hepatocyte apoptosis in rats with obstructive jaundice.

Obstructive jaundice (OJ) is a common disease in clinical surgery. The present study aimed to determine the effects of dexmedetomidine (Dex) on hepatocyte apoptosis in rats with OJ and also to explore the underlying mechanism. A total of 30 adult male Sprague Dawley rats were randomly divided into 3 groups: Sham group, bile duct ligation (BDL) group, and BDL+Dex group. The serum liver function index, expression levels of serum inflammatory factor interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and the liver pathological changes were compared amongst groups. The serum liver function index and expression levels of inflammatory factors in the BDL group and BDL+Dex group were higher compared with the sham group. The serum liver function index and expression levels of inflammatory factors were lower in the BDL+Dex group compared with the BDL group. The severity of hepatic injury was diminished in the BDL+Dex group compared with the BDL group. Compared with the sham group, the hepatocyte apoptosis rate increased significantly in the BDL group and BDL+Dex group. The present findings suggested that Dex improved the liver function of rats with OJ, reduced the production of inflammatory factors and inhibited the apoptosis of hepatocytes. Dex demonstrated a protective effect on liver damage potentially via activation of the phosphoinositide 3-kinase/protein kinase B signaling pathway.

Dynamics of interactive wild and sterile mosquitoes with time delay.

We develop a delay differential equation model for the interactive wild and sterile mosquitoes. Different from the existing modelling studies, we assume that only those sexually active sterile mosquitoes play a role for the interactive dynamics. We consider the cases where the release amount is either constant or described by a given function of time. For the constant releases, we establish a threshold of releases to determine whether the wild mosquito suppression succeeds or fails. We study the existence and stability of the model equilibria. When the releases are described by given functions, the trivial equilibrium is no longer globally but locally uniformly asymptotically stable if the amount of releases is below the threshold whereas it is still globally uniformly asymptotically stable if the release amount is above the threshold. Numerical examples demonstrating the model dynamical features and brief discussions of our findings are also provided.

Incompatible and sterile insect techniques combined eliminate mosquitoes.

The radiation-based sterile insect technique (SIT) has successfully suppressed field populations of several insect pest species, but its effect on mosquito vector control has been limited. The related incompatible insect technique (IIT)-which uses sterilization caused by the maternally inherited endosymbiotic bacteria Wolbachia-is a promising alternative, but can be undermined by accidental release of females infected with the same Wolbachia strain as the released males. Here we show that combining incompatible and sterile insect techniques (IIT-SIT) enables near elimination of field populations of the world's most invasive mosquito species, Aedes albopictus. Millions of factory-reared adult males with an artificial triple-Wolbachia infection were released, with prior pupal irradiation of the released mosquitoes to prevent unintentionally released triply infected females from successfully reproducing in the field. This successful field trial demonstrates the feasibility of area-wide application of combined IIT-SIT for mosquito vector control.

Use of age-stage structural models to seek optimal Wolbachia-infected male mosquito releases for mosquito-borne disease control.

Due to the lack of vaccines and effective clinical cures, current methods to control mosquito-borne viral diseases such as dengue and Zika are primarily targeting to eradicate the major mosquito vectors. However, traditional means, including larval source reduction and applications of insecticides etc, are not sufficient to keep vector population density below the epidemic risk threshold. An innovative and operational strategy is to release Wolbachia-infected male mosquitoes into wild areas to sterilize wild female mosquitoes by cytoplasmic incompatibility. To help design optimal release strategies before large scale and expensive operations, we started with an age-stage discrete model to track daily abundances of wild female mosquitoes, which fitted the field data collected by Guangzhou Center for Disease Control and Prevention from 2015 to 2017 with an average Pearson correlation coefficient 0.7283. Then, we modeled the Wolbachia interference by introducing the proportional releases of Wolbachia-infected males, and eight optimal release policies which guarantee more than 95% suppression efficiency were sought. Finally, we assessed the robustness of the optimality of the eight release policies by allowing the migration of females or the contamination of Wolbachia-infected females by two further extended mathematical models.

Linking dynamical complexities from activation signals to transcription responses.

The transcription of inducible genes involves signalling pathways that induce DNA binding of the downstream transcription factors to form functional promoter states. How the transcription dynamics is linked to the temporal variations of activation signals is far from being fully understood. In this work, we develop a mathematical model with multiple promoter states to address this question. Each promoter state has its own activation and inactivation rates and is selected randomly with a probability that may change in time. Under the activation of constant signals, our analysis shows that if only the activation rates differ among the promoter states, then the mean transcription level m(t) displays only a monotone or monophasic growth pattern. In a sharp contrast, if the inactivation rates change with the promoter states, then m(t) may display multiphasic growth patterns. Upon the activation of signals that oscillate periodically, m(t) also oscillates later, almost periodically at the same frequency, but the magnitude decreases with frequency and is almost completely attenuated at high frequencies. This gives a surprising indication that multiple promoter states could filter out the signal oscillation and the noise in the random promoter state selection, as observed in the transcription of a gene activated by p53 in breast carcinoma cells. Our approach may help develop a theoretical framework to integrate coherently the genetic circuit with the promoter states to elucidate the linkage from the activation signal to the temporal profile of transcription outputs.

The nonlinear dynamics and fluctuations of mRNA levels in cell cycle coupled transcription.

Gene transcription is a noisy process, and cell division cycle is an important source of gene transcription noise. In this work, we develop a mathematical approach by coupling transcription kinetics with cell division cycles to delineate how they are combined to regulate transcription output and noise. In view of gene dosage, a cell cycle is divided into an early stage [Formula: see text] and a late stage [Formula: see text]. The analytical forms for the mean and the noise of mRNA numbers are given in each stage. The analysis based on these formulas predicts precisely the fold change r* of mRNA numbers from [Formula: see text] to [Formula: see text] measured in a mouse embryonic stem cell line. When transcription follows similar kinetics in both stages, r* buffers against DNA dosage variation and r* ∈ (1, 2). Numerical simulations suggest that increasing cell cycle durations up-regulates transcription with less noise, whereas rapid stage transitions induce highly noisy transcription. A minimization of the transcription noise is observed when transcription homeostasis is attained by varying a single kinetic rate. When the transcription level scales with cellular volume, either by reducing the transcription burst frequency or by increasing the burst size in [Formula: see text], the noise shows only a minor variation over a wide range of cell cycle stage durations. The reduction level in the burst frequency is nearly a constant, whereas the increase in the burst size is conceivably sensitive, when responding to a large random variation of the cell cycle durations and the gene duplication time.