Microglial activation-mediated neuroinflammation is one of the essential pathogenic mechanisms of sepsis-associated encephalopathy (SAE). Mounting evidence suggests that high mobility group box-1 ...protein (HMGB1) plays a pivotal role in neuroinflammation and SAE, yet the mechanism by which HMGB1 induces cognitive impairment in SAE remains unclear. Therefore, this study aimed to investigate the mechanism of HMGB1 underlying cognitive impairment in SAE.
An SAE model was established by cecal ligation and puncture (CLP); animals in the sham group underwent cecum exposure alone without ligation and perforation. Mice in the inflachromene (ICM) group were continuously injected with ICM intraperitoneally at a daily dose of 10 mg/kg for 9 days starting 1 h before the CLP operation. The open field, novel object recognition, and Y maze tests were performed on days 14-18 after surgery to assess locomotor activity and cognitive function. HMGB1 secretion, the state of microglia, and neuronal activity were measured by immunofluorescence. Golgi staining was performed to detect changes in neuronal morphology and dendritic spine density. In vitro electrophysiology was performed to detect changes in long-term potentiation (LTP) in the CA1 of the hippocampus. In vivo electrophysiology was performed to detect the changes in neural oscillation of the hippocampus.
CLP-induced cognitive impairment was accompanied by increased HMGB1 secretion and microglial activation. The phagocytic capacity of microglia was enhanced, resulting in aberrant pruning of excitatory synapses in the hippocampus. The loss of excitatory synapses reduced neuronal activity, impaired LTP, and decreased theta oscillation in the hippocampus. Inhibiting HMGB1 secretion by ICM treatment reversed these changes.
HMGB1 induces microglial activation, aberrant synaptic pruning, and neuron dysfunction in an animal model of SAE, leading to cognitive impairment. These results suggest that HMGB1 might be a target for SAE treatment.
The brown planthopper, Nilaparvata lugens, is an economically important pest on rice in Asia. Chemical control is still the most efficient primary way for rice planthopper control. However, due to ...the intensive use of insecticides to control this pest over many years, resistance to most of the classes of chemical insecticides has been reported. In this article, we report on the status of eight insecticides resistance in Nilaparvata lugens (Stål) collected from China over the period 2012-2016. All of the field populations collected in 2016 had developed extremely high resistance to imidacloprid, thiamethoxam, and buprofezin. Synergism tests showed that piperonyl butoxide (PBO) produced a high synergism of imidacloprid, thiamethoxam, and buprofezin effects in the three field populations, YA2016, HX2016, and YC2016. Functional studies using both double-strand RNA (dsRNA)-mediated knockdown in the expression of CYP6ER1 and transgenic expression of CYP6ER1 in Drosophila melanogaster showed that CYP6ER1 confers imidacloprid, thiamethoxam and buprofezin resistance. These results will be beneficial for effective insecticide resistance management strategies to prevent or delay the development of insecticide resistance in brown planthopper populations.
Agrobacterium rhizogenes-mediated (ARM) transformation is a highly efficient technique for generating composite plants composed of transgenic roots and wild-type shoot, providing a powerful tool for ...studying root biology. The ARM transformation has been established in many plant species, including soybean. However, traditional transformation of soybean, transformation efficiency is low. Additionally, the hairy roots were induced in a medium, and then the generated composite plants were transplanted into another medium for growth. This two-step operation is not only time-consuming, but aggravates contamination risk in the study of plant-microbe interactions.
Here, we report a one-step ARM transformation method with higher transformation efficiency for generating composite soybean plants. Both the induction of hairy roots and continuous growth of the composite plants were conducted in a single growth medium. The primary root of a 7-day-old seedling was decapitated with a slanted cut, the residual hypocotyl (maintained 0.7-1 cm apical portion) was inoculated with A. rhizogenes harboring the gene construct of interest. Subsequently, the infected seedling was planted into a pot with wet sterile vermiculite. Almost 100% of the infected seedlings could produce transgenic positive roots 16 days post-inoculation in 7 tested genotypes. Importantly, the transgenic hairy roots in each composite plant are about three times more than those of the traditional ARM transformation, indicating that the one-step method is simpler in operation and higher efficiency in transformation. The reliability of the one-step method was verified by CRISPR/Cas9 system to knockout the soybean Rfg1, which restricts nodulation in Williams 82 (Nod-) by Sinorhizobium fredii USDA193. Furthermore, we applied this method to analyze the function of Arabidopsis YAO promoter in soybean. The activity of YAO promoter was detected in whole roots and stronger in the root tips. We also extended the protocol to tomato.
We established a one-step ARM transformation method, which is more convenient in operation and higher efficiency (almost 100%) in transformation for generating composite soybean plants. This method has been validated in promoter functional analysis and rhizobia-legume interactions. We anticipate a broad application of this method to analyze root-related events in tomato and other plant species besides soybean.
Simply the best: The title reaction has been achieved by asymmetric rhodium catalysis employing an extremely simple, chiral N‐(sulfinyl)cinnamylamine ligand. A variety of highly enantioenriched, ...tertiary α‐hydroxy carbonyl derivatives were easily accessed at room temperature under mild conditions with enantioselectivities of up to 99 %.
Background and Aims
Epidemics pose a great challenge to health care of patients. However, the impact of unprecedented situation of COVID‐19 outbreak on health care of inflammatory bowel disease (IBD) ...patients in real‐world setting has seldom been investigated.
Methods
We performed an observational study in a tertiary referral IBD center in China. The mode of health care and medication use was compared before and after COVID‐19 outbreak. Electronic questionnaire surveys were performed among gastroenterologists and IBD patients to investigate the impact of COVID‐19 outbreak on their attitudes towards telemedicine.
Results
COVID‐19 outbreak resulted in substantial decrease of patients participating in standard face‐to‐face visit during 1 month post‐outbreak (n = 51) than pre‐outbreak (n = 249), whereas the participation in telemedicine was significantly higher than comparable period in 2019 (414 vs 93). During the 1 month after COVID‐19 outbreak, 39 (39/56, 69.6%) patients had their infliximab infusion postponed with the mean delay of 3 weeks. The immunomodulator use was similar between pre‐outbreak and post‐outbreak. Six elective surgeries were postponed for a median of 43 days. In post‐outbreak period, 193 (193/297, 64.98%) of the surveyed physicians have used telemedicine with an increase of 18.9% compared with 46.13% (137/292) in the pre‐outbreak period (P < 0.001); 331 (331/505, 65.54%) of the surveyed IBD patients supported that the use of telemedicine should be increased in future health care.
Conclusion
COVID‐19 outbreak resulted in a great change in health‐care access among IBD patients including decrease in standard face‐to‐face visit and delay of biologics use. There was an increased use and need of telemedicine after COVID‐19 outbreak.
Cells contain dozens of major organelles and thousands of other structures, many of which vary extensively in their number, size, shape and spatial distribution. This complexity and variation ...dramatically complicates the use of both traditional and deep learning methods to build accurate models of cell organization. Most cellular organelles are distinct objects with defined boundaries that do not overlap, while the pixel resolution of most imaging methods is n sufficient to resolve these boundaries. Thus while cell organization is conceptually object-based, most current methods are pixel-based. Using extensive image collections in which particular organelles were fluorescently labeled, deep learning methods can be used to build conditional autoencoder models for particular organelles. A major advance occurred with the use of a U-net approach to make multiple models all conditional upon a common reference, unlabeled image, allowing the relationships between different organelles to be at least partially inferred.
We have developed improved Generative Adversarial Networks-based approaches for learning these models and have also developed novel criteria for evaluating how well synthetic cell images reflect the properties of real images. The first set of criteria measure how well models preserve the expected property that organelles do not overlap. We also developed a modified loss function that allows retraining of the models to minimize that overlap. The second set of criteria uses object-based modeling to compare object shape and spatial distribution between synthetic and real images. Our work provides the first demonstration that, at least for some organelles, deep learning models can capture object-level properties of cell images.
http://murphylab.cbd.cmu.edu/Software/2022_insilico.
Supplementary data are available at Bioinformatics online.
During retinal microsurgery, surgeons cannot adequately visualize subsurface anatomical structures. In our previous work, a customized B-mode optical coherence tomography (OCT) probe was integrated ...into an ophthalmic robotic system to provide depth perception. This paper presents new approaches for implementing and achieving real-time feedback and assistive robotic control based on B-mode OCT imaging. The robotic system was comprised of a parallel robot, a micro-injection tool, and a telemanipulation master interface. A method for calibrating the B-mode OCT image scaling and distortion was presented using thin plate splines. Determining the OCT scanning plane relative to the robot base frame is presented through experiments and analyzed for sensitivity. A dual-rate controller using low frequency OCT feedback and high frequency position servoing was presented and tested for accuracy and latency. Three-dimensional assistive telemanipulation virtual fixtures based on microscope and OCT feedback are presented. The experimental evaluation demonstrated following target anatomy and semi-automated micro-injection. These results present the key steps towards achieving an integrated system for OCT feedback control using a miniature intraocular B-mode probe.
Background and Purpose
Atopic dermatitis is a common chronic pruritic inflammatory disease of the skin involving neuro‐immune communication. Neuronal mechanism‐based therapeutic treatments remain ...lacking. We investigated the efficacy of intravenous lidocaine therapy on atopic dermatitis and the underlying neuro‐immune mechanism.
Experimental Approach
Pharmacological intervention, immunofluorescence, RNA‐sequencing, genetic modification and immunoassay were performed to dissect the neuro‐immune basis of itch and inflammation in atopic dermatitis‐like mouse model and in patients.
Key Results
Lidocaine alleviated skin lesions and itch in both atopic dermatitis patients and calcipotriol (MC903)‐induced atopic dermatitis model by blocking subpopulation of sensory neurons. QX‐314, a charged NaV blocker that enters through pathologically activated large‐pore ion channels and selectivity inhibits a subpopulation of sensory neurons, has the same effects as lidocaine in atopic dermatitis model. Genetic silencing NaV1.8‐expressing sensory neurons was sufficient to restrict cutaneous inflammation and itch in the atopic dermatitis model. However, pharmacological blockade of TRPV1‐positive nociceptors only abolished persistent itch but did not affect skin inflammation in the atopic dermatitis model, indicating a difference between sensory neuronal modulation of skin inflammation and itch. Inhibition of activity‐dependent release of calcitonin gene‐related peptide (CGRP) from sensory neurons by lidocaine largely accounts for the therapeutic effect of lidocaine in the atopic dermatitis model.
Conclusion and Implications
NaV1.8+ sensory neurons play a critical role in pathogenesis of atopic dermatitis and lidocaine is a potential anti‐inflammatory and anti‐pruritic agent for atopic dermatitis. A dissociable difference for sensory neuronal modulation of skin inflammation and itch contributes to further understanding of pathogenesis in atopic dermatitis.
Type 2 bradykinin receptor (B2R) is an essential G protein-coupled receptor (GPCR) that regulates the cardiovascular system as a vasodepressor. Dysfunction of B2R is also closely related to cancers ...and hereditary angioedema (HAE). Although several B2R agonists and antagonists have been developed, icatibant is the only B2R antagonist clinically used for treating HAE. The recently determined structures of B2R have provided molecular insights into the functions and regulation of B2R, which shed light on structure-based drug design for the treatment of B2R-related diseases. In this review, we summarize the structure and function of B2R in relation to drug discovery and discuss future research directions to elucidate the remaining unknown functions of B2R dimerization.
Percutaneous kyphoplasty (PKP) is the first-line treatment for osteoporotic vertebral compression fractures (OVCFs) that can immediately relieve pain and allow the quick recovery of lost mobility. ...However, some studies reported that after PKP, the incidence of vertebral refracture, particularly adjacent vertebral fracture (AVF), was high. Our previous meta-analysis suggested that the risks for vertebral refracture and AVF did not increase after percutaneous vertebral augmentation in OVCF patients. Despite the negative results of our meta-analysis, there is still significant evidence regarding the relationship between kyphoplasty and AVF, so a new prospective cohort study is warranted. In addition, in our previous retrospective study, we found that advanced age, female sex and low oestradiol (E
) concentrations might be related to the occurrence of postoperative vertebral refracture after PKP. To sufficiently evaluate the probable factors involved in the occurrence of postoperative vertebral refracture, we designed this prospective study.
This is a prospective cohort study of patients admitted for PKP to treat painful OVCFs. The baseline data, including demographic information, lifestyle, bone metabolic status, sex hormone and sex hormone-binding globulin (SHBG) levels, and clinical characteristics will be collected at the time of enrolment. Surgical features of PKP will be recorded on the operation day. Lifestyle, bone metabolic status, sex hormone levels, and SHBG levels will be assessed during the follow-up period at 1 m, 3 m, 12 m, and 24 m postoperatively. Patients suffering from acutely aggravated back pain will be referred to an orthopaedist, and refractured vertebrae will be confirmed by magnetic resonance imaging and computed tomography. The primary outcome will be the incidence of vertebral refracture. Multivariate analyses will be carried out to evaluate the variables that are independently correlated with vertebral refracture.
To evaluate the risk of postoperative refracture preoperatively and to identify the surgical points related to postoperative refracture, this study will explore the risk factors related to vertebral refracture after PKP. The results may provide new information about defining OVCF patients suitable for PKP treatment.
ChiCTR-ROC-17011562 . Registered on July 4th, 2017.
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