Metabotropic glutamate receptor 5 promotes blood-brain barrier recovery after traumatic brain injury.

Blood-brain barrier (BBB) impairment and glutamate release are two pathophysiological features of traumatic brain injury (TBI), contributing to secondary brain damage and neuroinflammation. However, our knowledge of BBB integrity damage and dysfunction are still limited due to the diverse and fluctuating expression of glutamate receptors after trauma. Here, we confirmed the downregulation of metabotropic glutamate receptor 5 (mGluR5) on microvascular endothelial cell within the acute phase of TBI, and the recovered mGluR5 levels on BBB was positively associated with blood perfusion and neurological recovery. In whole body mGluR5-knockout mice, BBB dysfunction and neurological deficiency were exacerbated after TBI compared with wild type mice. In terms of mechanism, the amino acid sequence 201-259 of cytoskeletal protein Alpha-actinin-1 (ACTN1) interacted with mGluR5, facilitating mGluR5 translocation from cytoplasmic compartment to plasma membrane in endothelial cells. Activation of plasma membrane mGluR5 triggers the PLC/PKCµ/c-Jun signaling pathway, leading to increased expression of the tight junction-actin cytoskeleton connecting protein zonula occludens-1 (ZO-1). Our findings uncover a novel mechanism mediated by membrane and cytoplasmic mGluR5 in endothelial cell integrity maintenance and repair, providing the potential therapeutic target for TBI treatment targeting at mGluR5 and mGluR5/ACTN1 complex in BBB.

Change and challenge: An online course in Medical Biochemistry and Molecular Biology.

The development of information technology and portable devices has sparked a revolution in the field of education, facilitating access to diverse educational resources and lifelong learning. In particular, the COVID-19 pandemic has accelerated the transition from face-to-face to distance teaching, which requires online education to be provided worldwide. Biochemistry and Molecular Biology are key basic medical courses in laboratory-based science that cover complicated theories and applications. The balance between traditional and online courses, and the effectiveness of online courses, are fundamental to the teaching quality of Biochemistry and Molecular Biology. In this study, we explored the concepts, designs, and practices of a new blended online course and identified potential challenges. We hope that our experiences will provide new ideas for online teaching and promote teaching reform and the development of Medical Biochemistry and Molecular Biology education.

Sinomenine alleviates lipopolysaccharide-induced acute lung injury via a PPARß/δ-dependent mechanism.

Evidence is mounting that sinomenine and peroxisome proliferator-activated receptor ß/δ (PPARß/δ) are effective against lipopolysaccharide (LPS)-induced acute lung injury (ALI) via anti-inflammatory properties. However, it is unknown whether PPARß/δ plays a role in the protective effect of sinomenine on ALI. Here, we initially observed that preemptive administration of sinomenine markedly alleviated lung pathological changes, pulmonary edema and neutrophil infiltration, accompanied by inhibition of the expression of the pro-inflammatory cytokines Tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6), which were largely reversed following the addition of a PPARß/δ antagonist. Subsequently, we also noticed that sinomenine upregulated adenosine A2A receptor expression in a PPARß/δ-dependent manner in LPS-stimulated bone marrow-derived macrophages (BMDMs). Further investigation indicated that PPARß/δ directly bound to the functional peroxisome proliferator responsive element (PPRE) in the adenosine A2A receptor gene promoter region to enhance the expression of the adenosine A2A receptor. Sinomenine was identified as a PPARß/δ agonist. It could bind with PPARß/δ, and promote the nuclear translocation and transcriptional activity of PPARß/δ. In addition, combined treatment with sinomenine and an adenosine A2A receptor agonist exhibited synergistic effects and better protective roles than their single use against ALI. Taken together, our results reveal that sinomenine exerts advantageous effects on ALI by activating of PPARß/δ, with the subsequent upregulation of adenosine A2A receptor expression, and provide a novel and potential therapeutic application for ALI.

A personalized pharmaco-epistatic network model of precision medicine.

Precision medicine, the utilization of targeted treatments to address an individual's disease, relies on knowledge about the genetic cause of that individual's drug response. Here, we present a functional graph (FunGraph) theory to chart comprehensive pharmacogenetic architecture for each and every patient. FunGraph is the combination of functional mapping - a dynamic model for genetic mapping and evolutionary game theory guiding interactive strategies. It coalesces all pharmacogenetic factors into multilayer and multiplex networks that fully capture bidirectional, signed and weighted epistasis. It can visualize and interrogate how epistasis moves in the cell and how this movement leads to patient- and context-specific genetic architecture in response to organismic physiology. We discuss the future implementation of FunGraph to achieve precision medicine.

Genome-wide characterization and identification of Trihelix transcription factors and expression profiling in response to abiotic stresses in Chinese Willow (Salix matsudana Koidz).

Trihelix transcription factors (TTF) are a class of light-responsive proteins with a typical triple-helix structure (helix-loop-helix-loop-helix). Members of this gene family play an important role in plant growth and development, especially in various abiotic stress responses. Salix matsudana Koidz is an allotetraploid ornamental forest tree that is widely planted for its excellent resistance to stress, but no studies on its Trihelix gene family have been reported. In this study, the Trihelix gene family was analyzed at the genome-wide level in S. matsudana. A total of 78 S. matsudana Trihelix transcription factors (SmTTFs) were identified, distributed on 29 chromosomes, and classified into four subfamilies (GT-1, GT-2, SH4, SIP1) based on their structural features. The gene structures and conserved functional domains of these Trihelix genes are similar in the same subfamily and differ between subfamilies. The presence of multiple stress-responsive cis-elements on the promoter of the S. matsudana Trihelix gene suggests that the S. matsudana Trihelix gene may respond to abiotic stresses. Expression pattern analysis revealed that Trihelix genes have different functions during flooding stress, salt stress, drought stress and low temperature stress in S. matsudana. Given that SmTTF30, as a differentially expressed gene, has a faster response to flooding stress, we selected SmTTF30 for functional studies. Overexpression of SmTTF30 in Arabidopsis thaliana (Arabidopsis) enhances its tolerance to flooding stress. Under flooding stress, the leaf cell activity and peroxidase activity (POD) of the overexpression strain were significantly higher than the leaf cell activity and POD of the wild type, and the malondialdehyde (MDA) content was significantly lower than the MDA content of the wild type. Thus, these results suggest that SmTTF30 enhances plant flooding tolerance and plays a positive regulatory role in plant flooding tolerance.

Neglect of preschool children in urban area of Xi an under the background of multi-child policy / 中国学校卫生

Objective@#To understand the situation of neglect of preschool children in the urban area of Xi an under the background of multi child policy, so as to provide a reference for making effective prevention.@*Methods@#In Novmber 2022, according to the multi stage stratified cluster sampling principle, 2 450 parents of children aged 3-6 years were randomly selected from 7 urban areas of Xi an to participate in the questionnaire survey. A questionnaire survey was conducted using the "Neglect Evaluation Norms of 3-6 Years Old (Preschool) Children in Urban Areas of China". SPSS 18.0 software was used for statistical description, Chi square test and variance analysis.@*Results@#The total neglect rate of preschool children in the urban area of Xi an was 29.0% and the total neglect score was (37.58±8.44). There was no statistical difference in the neglect status of children in different grade groups ( χ 2/ F =1.61, 2.98, P >0.05). The neglect score of boys was higher than girls ( t =2.45, P <0.05). There was no statistical difference in the neglect rate and neglect score of boys and girls in other levels ( P >0.05); except for the significant difference in the neglect degree of medical treatment, education and safety ( t =2.01, 2.28, 2.02, P <0.05). The rate and score of neglect in multi-child families were higher than only-child families ( χ 2/ t = 13.68, -4.54, P <0.05). There were significant differences in the rate and degree of neglect of children with different birth order, which were "third and fourth-born>second-born>first-born" ( χ 2/ F = 10.84 , 2.79, P <0.05). The neglect rate and score of "single parent family" were significantly higher than that of "nuclear family" and "three-generation family" ( χ 2/ F =4.78, 2.79, P <0.05).@*Conclusion@#The neglect situation of preschool children in urban area of Xi an is still serious, especially in multi-child families. It should actively explore the risk factors and formulate effective intervention measures.

Histones of Neutrophil Extracellular Traps Induce CD11b Expression in Brain Pericytes Via Dectin-1 after Traumatic Brain Injury.

The brain pericyte is a unique and indispensable part of the blood-brain barrier (BBB), and contributes to several pathological processes in traumatic brain injury (TBI). However, the cellular and molecular mechanisms by which pericytes are regulated in the damaged brain are largely unknown. Here, we show that the formation of neutrophil extracellular traps (NETs) induces the appearance of CD11b+ pericytes after TBI. These CD11b+ pericyte subsets are characterized by increased permeability and pro-inflammatory profiles compared to CD11b- pericytes. Moreover, histones from NETs by Dectin-1 facilitate CD11b induction in brain pericytes in PKC-c-Jun dependent manner, resulting in neuroinflammation and BBB dysfunction after TBI. These data indicate that neutrophil-NET-pericyte and histone-Dectin-1-CD11b are possible mechanisms for the activation and dysfunction of pericytes. Targeting NETs formation and Dectin-1 are promising means of treating TBI.

Glutamate blunts cell-killing effects of neutrophils in tumor microenvironment.

Neutrophils are the first defenders of the innate system for injury and infection. They have gradually been recognized as important participants in tumor initiation and development due to their heterogeneity and plasticity. In the tumor microenvironment (TME), neutrophils can exert antitumor and protumor functions, depending on the surroundings. Tumor cells systemically alter intracellular amino acid (AA) metabolism and extracellular AA distribution to meet their proliferation need, leading to metabolic reprogramming and TME reshaping. However, the underlying mechanisms that determine how altered AAs affect neutrophils in TME are less-explored. Here, we identified that abundant glutamate releasing from tumor cells blunted neutrophils' cell-killing effects toward tumor cells in vitro and in vivo. Mass spectrometric detection, flow cytometry, and western blot experiments proved that increased levels of pSTAT3/RAB10/ARF4, mediated by glutamate, were accompanied with immunosuppressive phenotypes of neutrophils in TME. We also discovered that riluzole, an FDA-approved glutamate release inhibitor, significantly inhibited tumor growth by restoring neutrophils' cell-killing effects and decreasing glutamate secretion from tumor cells. These findings highlight the importance of tumor-released glutamate on neutrophil transformation in TME, providing new possible cancer treatments targeting altered glutamate metabolism.

Targeting metabotropic glutamate receptor 4 for cancer immunotherapy.

In this study, we report a novel role of metabotropic glutamate receptor 4 (GRM4) in suppressing antitumor immunity. We revealed in three murine syngeneic tumor models (B16, MC38, and 3LL) that either genetic knockout (Grm4−/−) or pharmacological inhibition led to significant delay in tumor growth. Mechanistically, perturbation of GRM4 resulted in a strong antitumor immunity by promoting natural killer (NK), CD4+, and CD8+ T cells toward an activated, proliferative, and functional phenotype. Single-cell RNA sequencing and T cell receptor profiling further defined the clonal expansion and immune landscape changes in CD8+ T cells. We further showed that Grm4−/− intrinsically activated interferon-γ production in CD8+ T cells through cyclic adenosine 3',5'-monophosphate (cAMP)/cAMP response element binding protein­mediated pathway. Our study appears to be of clinical significance as a signature of NKhigh-GRM4low and CD8high-GRM4low correlated with improved survival in patients with melanoma. Targeting GRM4 represents a new approach for cancer immunotherapy.

Rational evaluation of various epidemic models based on the COVID-19 data of China.

In this paper, based on the Akaike information criterion, root mean square error and robustness coefficient, a rational evaluation of various epidemic models/methods, including seven empirical functions, four statistical inference methods and five dynamical models, on their forecasting abilities is carried out. With respect to the outbreak data of COVID-19 epidemics in China, we find that before the inflection point, all models fail to make a reliable prediction. The Logistic function consistently underestimates the final epidemic size, while the Gompertz's function makes an overestimation in all cases. Towards statistical inference methods, the methods of sequential Bayesian and time-dependent reproduction number are more accurate at the late stage of an epidemic. And the transition-like behavior of exponential growth method from underestimation to overestimation with respect to the inflection point might be useful for constructing a more reliable forecast. Compared to ODE-based SIR, SEIR and SEIR-AHQ models, the SEIR-QD and SEIR-PO models generally show a better performance on studying the COVID-19 epidemics, whose success we believe could be attributed to a proper trade-off between model complexity and fitting accuracy. Our findings not only are crucial for the forecast of COVID-19 epidemics, but also may apply to other infectious diseases.

Adolescents' Social Media Use and Their Voluntary Garbage Sorting Intention: A Sequential Mediation Model.

Encouraging adolescents to sort garbage is vital for the sustainable development of the ecological environment. This study investigates the relationship between adolescents' social media use and their garbage sorting intention. A survey, in both online and paper-based versions, was distributed in 2020 in Shanghai and a total number of 605 valid responses were obtained. This study supports the proposed sequential mediation model, indicating that adolescents' social media use increased their garbage sorting intention via the serial mediation effect of objective and subjective knowledge and the perceived importance of garbage sorting. The current study and its findings provide important insights into the link between adolescents' social media use and their garbage sorting intention, particularly its underlying mechanism, by distinguishing knowledge into two specific types and introducing perceived importance into the conceptual model. Practical implications for improving adolescents' intention to sort garbage are also discussed.

Inhibitory Effects of Sulfated Polysaccharides from the Sea Cucumber Cucumaria Frondosa against Aß40 Aggregation and Cytotoxicity.

Abnormal aggregation and deposition of Aß is one of the causative agents for Alzheimer's disease. The development of inhibitors for Aß aggregation has been considered a possible method to prevent and treat Alzheimer's disease. Edible sea cucumbers contain many bioactive molecules, including saponins, phospholipids, peptides, and polysaccharides. Herein, we report that polysaccharides extracted from sea cucumber Cucumaria frondosa could reduce the aggregation and cytotoxicity of Aß40. By utilizing multiple biochemical and biophysical instruments, we found that the polysaccharides could inhibit the aggregation of Aß40. A chemical kinetics analysis further suggested that the major inhibitory effects of the polysaccharides were achieved by disassembling mature fibrils, which in turn reduced the cytotoxicity of Aß. These results suggested that the polysaccharides extracted from sea cucumber could be used as an effective inhibitor for Aß.

When machine learning meets multiscale modeling in chemical reactions.

Due to the intrinsic complexity and nonlinearity of chemical reactions, direct applications of traditional machine learning algorithms may face many difficulties. In this study, through two concrete examples with biological background, we illustrate how the key ideas of multiscale modeling can help to greatly reduce the computational cost of machine learning, as well as how machine learning algorithms perform model reduction automatically in a time-scale separated system. Our study highlights the necessity and effectiveness of an integration of machine learning algorithms and multiscale modeling during the study of chemical reactions.

Rational Design of a Cocktail of Inhibitors against Aß Aggregation.

It has been reported that many molecules could inhibit the aggregation of Aß (amyloid-ß) through suppressing either primary nucleation, secondary nucleation, or elongation processes. In order to suppress multiple pathways of Aß aggregation, we screened 23 small molecules and found two types of inhibitors with different inhibiting mechanisms based on chemical kinetics analysis. Trp-glucose conjugates (AS2) could bind with fibril ends while natural products (D3 and D4) could associate with monomers. A cocktail of these two kinds of molecules achieved co-inhibition of various fibrillar species and avoid unwanted interference.

Prediction of amyloid aggregation rates by machine learning and feature selection.

A novel data-based machine learning algorithm for predicting amyloid aggregation rates is reported in this paper. Based on a highly nonlinear projection from 16 intrinsic features of a protein and 4 extrinsic features of the environment to the protein aggregation rate, a feedforward fully connected neural network (FCN) with one hidden layer is trained on a dataset composed of 21 different kinds of amyloid proteins and tested on 4 rest proteins. FCN shows a much better performance than traditional algorithms, such as multivariable linear regression and support vector regression, with an average accuracy higher than 90%. Furthermore, by the correlation analysis and the principal component analysis, seven key features, folding energy, HP patterns for helix, sheet and helices cross membrane, pH, ionic strength, and protein concentration, are shown to constitute a minimum feature set for characterizing the amyloid aggregation kinetics.

A study on the neurodevelopment outcomes of late preterm infants.

BACKGROUND: The study is intended to fill the knowledge gap about the neuropsychology and neuromotor developmental outcomes, and identify the perinatal risk factors for late preterm infants (LPIs 34~36 weeks GA) born with uncomplicated vaginal birth at the age of 24 to 30 months. METHODS: The parents/guardians of 102 late preterm infants and 153 term infants, from 14 community health centers participated in this study. The Modified Checklist for Autism in Toddlers (M-CHAT) questionnaire, the Chinese version of Gesell Development Diagnosis Scale (GDDS), and the Sensory Integration Schedule (SIS), a neurological examination for motor disorders (MD) were carried out. Infants screening positive to the M-CHAT were referred to specialist autism clinics. RESULTS: Forty-six LPIs (45.1%) scored low in GDDS. Nine LPIs (8.8%) scored positive on M-Chat. 8.8% of LPIs (9 out of 102) were diagnosed MD (p <  0.05). Compared with their full-term peers, LPIs had statistically lower scores in GDDS and the Child Sensory Integration Checklist. LPIs who had positive results on M-CHAT showed unbalanced abilities in every part of GDDS. Risk factors of twin pregnancies, pregnancy induced hypertension and premature rupture of membranes had negative correlation with GDDS (all p <  0.05). Birth weight and gestational age were positively correlated with GDDS. CONCLUSIONS: LPIs shall be given special attention as compared to normal deliveries, as they are at increased risk of neurodevelopment impairment, despite being born with no major problems. Some perinatal factors such as twin pregnancies, and pregnancy induced hypertension etc. have negative effects on their neurodevelopment. Regular neurodevelopmental follow- up and early intervention can benefit their long term outcomes.

Transplantation with mGluR5 deficiency bone marrow displays antidepressant-like effect in C57BL/6J mice.

Antidepressant-like effects of metabotropic glutamate receptor 5 (mGluR5) have been verified by specific antagonists or whole body knock-out (KO) mice. Previous experiments indicate that blocking mGluR5 exerts antidepressant-like effects through neuronal mechanisms, like modulating NMDA receptor activity or 5-HT system. Here we found that transplanting bone marrow from mGluR5 KO mice to WT mice could also show antidepressant-like effects, which were confirmed by sucrose preference test and tail suspension test. Furthermore, mGluR5 deficiency dramatically inhibits cytokines release from bone marrow cells, such as IL-1ß, TNF-α and IL-6, alleviating proinflammatory responses in LPS-induced depression model. In addition, inhibited cytokines could decrease the activation of brain endothelial cells in ERK-dependent manner. These data provide the evidence that blocking mGluR5 could improve depression through inhibiting peripheral immune responses, confirming the causal relationship between peripheral immune phenotype and brain behavior.

Differential Modulation of the Aggregation of N-Terminal Truncated Aß using Cucurbiturils.

Modulating the aggregation of Aß has long been considered to be one of the potential methods to treat Alzheimer's disease (AD). It has been found that different Aß species, including N-terminal truncated or/and modified Aß, co-exist in the brain of AD patients. Yet, there is currently little detailed work about the specific modulation of these Aß species which hinders us to understand their roles in patients' brain. Using thioflavin T (ThT) kinetics and transmission electron microscope, here we showed that cucurbit[7]uril and cucurbit[8]uril could inhibit the aggregation of both Aß4-40 and Aß1-40 through host-guest interactions. Chemical kinetics analysis suggested that this happened through inhibiting the elongation process by binding with fibril ends. In addition, cucurbiturils showed greater capability on the inhibition of Aß4-40 than Aß1-40 , which was possibly due to the N-terminal phenylalanine residue of Aß4-40 . Our work provided new insights for the development of host-guest chemistry based inhibitors for the aggregation of different Aß species.

Neutrophils in traumatic brain injury (TBI): friend or foe?

Our knowledge of the pathophysiology about traumatic brain injury (TBI) is still limited. Neutrophils, as the most abundant leukocytes in circulation and the first-line transmigrated immune cells at the sites of injury, are highly involved in the initiation, development, and recovery of TBI. Nonetheless, our understanding about neutrophils in TBI is obsolete, and mounting evidences from recent studies have challenged the conventional views. This review summarizes what is known about the relationships between neutrophils and pathophysiology of TBI. In addition, discussions are made on the complex roles as well as the controversial views of neutrophils in TBI.

Metabotropic glutamate receptor 5 deficiency inhibits neutrophil infiltration after traumatic brain injury in mice.

Both brain native inflammatory cells and infiltrated peripheral white blood cells (WBCs) are primary participants in the brain inflammatory damage post-TBI. Metabotropic glutamate receptor 5 (mGluR5) has been reported to regulate microglias and astrocytes to affect inflammation after TBI, but its effect on modulating infiltrated peripheral WBCs remains unclear. In a mouse moderate TBI model, we found that mGluR5 knockout (KO) significantly reduced neutrophil infiltration and inflammatory cytokine expression in the brain at 24 hours post TBI, which was accompanied by improved neurological dysfunction. Further investigation indicated that mGluR5 KO reduced the permeability of blood-brain barrier (BBB), the entrance for neutrophils to enter brain, and markedly decreased the mRNA levels of neutrophil-associated chemokines in brain tissue, including CXCL1, CXCL2, CCL2, CCL4 and CCL5. Using brain microvascular endothelial cells (BMECs), neutrophils and a BBB model in vitro, we confirmed the inhibitory effect of mGluR5 deficiency on neutrophil infiltration and demonstrated that blockade of protein kinase C (PKC) signaling was involved in it. These results provide insight into the role of mGluR5 in the regulation of inflammation in the acute phase of TBI, which may provide novel clues for TBI therapy.