Characterizing the complete mitogenome of Odontothrips phaseoli (Thysanoptera: Thripidae) and its mitochondrial phylogeny.

Described originally from Heilongjiang, China, Odontothrips phaseoli is a potential pest of threatening bean plant in northern China. The complete mitochondrial genome of O. phaseoli was sequenced and assembled, with a total length of 15,540 bp. Within this genome, 37 genes have been identified: 13 PCGs, 22 tRNAs, two rRNAs, and two putative control regions. Most PCGs terminate with TAA, while four genes (atp8, nad1, nad2 and nad4) use an incomplete 'T' and nad6 employs TAG as the stop codon. Compared to the mitogenome of the ancestral insect, O. phaseoli displays significant gene rearrangement. However, it retains three conserved gene blocks in common with its related species, Megalurothrips usitatus, both of which belong to the Megalurothrips genus-group. The phylogenetic tree, constructed based on the entire mitogenome dataset of all thrips species available in NCBI, shows that the two species cluster closely together. This alignment might underscore the close link between gene arrangements and the phylogeny relationships.

Study of the internal mechanism of attention focus affecting countermovement jump performance based on muscle synergy theory.

OBJECTIVE: The purpose of this study was to explain the internal mechanism of attention focus affecting performance of countermovement jump based on muscle synergy theory. METHODS: Participants involved untrained group(N = 10) and high-level group(N = 11). Subjects performed countermovement jump with internal attention focus instruction (IF), external distal attention focus instruction (EDF), and external proximal attention focus instruction (EPF). The electromyography (EMG) signals of the dominant vastus lateralis muscle (VL), semitendinosus muscle (ST), tibial anterior muscle (TA), rectus femoris muscle (RF), and medial gastrocnemius (MG) were recorded. The non-negative matrix factorization was used to extract muscle synergy. RESULTS: 1) Attention focus did not affect countermovement jump performance and the number of muscle synergy in the high-level group (P>0.05). 2) Attention focus instructions affected the untrained group countermovement jump (P<0.05). and EDF and EPF reduced the number of muscle synergy. 3)The Cohen's d of EDF (0.269) was less than EPF (0.377) in untrained group. CONCLUSION: For the untrained people, the improved motor performance caused by attention focus resembled the adaptive changes that occur with long-term training. The reason why an EDF is superior to EPF is that the former produces more thorough changes in muscle synergy.

A Single-Frame Deflectometry Method for Online Inspection of Light-Transmitting Components.

Transparent materials are widely used in industrial applications, such as construction, transportation, and optics. However, the complex optical properties of these materials make it difficult to achieve precise surface form measurements, especially for bulk surface form inspection in industrial environments. Traditional structured light-based measurement methods often struggle with suboptimal signal-to-noise ratios, making them ineffective. Currently, there is a lack of efficient techniques for real-time inspection of such components. This paper proposes a single-frame measurement technique based on deflectometry for large-size transparent surfaces. It utilizes the reflective characteristics of the measured surface, making it independent of the surface's diffuse reflection properties. This fundamentally solves the issues associated with signal-to-noise ratios. By discretizing the phase map, it separates the multiple surface reflection characteristics of transparent devices, enabling transparent device measurement. To meet the requirements of industrial dynamic measurement, this technique only needs a simple and low-cost system structure, which contains just two cameras for image capture. It does not require phase shifting to complete the measurement, making it independent of the screen and having the potential for larger surface measurement. The proposed method was used to measure a 400mm aperture automobile glass, and the results showed that it is able to achieve a measurement accuracy on the order of 10 µ m. The method proposed in this paper overcomes the influence of surface reflection on transparent objects and significantly improves the efficiency and accuracy of large-sized transparent surface measurements by using a single-frame image measurement. Moreover, this method shows promise for broader applications, including measurements of lenses and HUD (Heads-Up Display) components, showcasing significant potential for industrial applications.

Development of a Time-Resolved Fluorescence Resonance Energy Transfer ultra-high throughput screening assay for targeting SYK and FCER1G interaction.

The spleen tyrosine kinase (SYK) and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) interaction has a major role in the normal innate and adaptive immune responses, but dysregulation of this interaction is implicated in several human diseases, including autoimmune disorders, hematological malignancies, and Alzheimer's Disease. Development of small molecule chemical probes could aid in studying this pathway both in normal and aberrant contexts. Herein, we describe the miniaturization of a time-resolved fluorescence resonance energy transfer (TR-FRET) assay to measure the interaction between SYK and FCER1G in a 1536-well ultrahigh throughput screening (uHTS) format. The assay utilizes the His-SH2 domains of SYK, which are indirectly labeled with anti-His-terbium to serve as TR-FRET donor and a FITC-conjugated phosphorylated ITAM domain peptide of FCER1G to serve as acceptor. We have optimized the assay into 384-well HTS format and further miniaturized the assay into a 1536-well uHTS format. Robust assay performance has been achieved with a Z' factor > 0.8 and signal-to-background (S/B) ratio > 15. The utilization of this uHTS TR-FRET assay for compound screening has been validated by a pilot screening of 2,036 FDA-approved and bioactive compounds library. Several primary hits have been identified from the pilot uHTS. One compound, hematoxylin, was confirmed to disrupt the SYK/FECR1G interaction in an orthogonal protein-protein interaction assay. Thus, our optimized and miniaturized uHTS assay could be applied to future scaling up of a screening campaign to identify small molecule inhibitors targeting the SYK and FCER1G interaction.

Based on Network Pharmacology and Molecular Docking, the Active Components, Targets, and Mechanisms of Flemingia philippinensis in Improving Inflammation Were Excavated.

Flemingia philippinensis, a polyphenol-rich plant, holds potential for improving inflammation, but its mechanisms are not well understood. Therefore, this study employed network pharmacology and molecular docking to explore the mechanism by which Flemingia philippinensis ameliorates inflammation. In this study, 29 kinds of active ingredients were obtained via data mining. Five main active components were screened out for improving inflammation, which were flemichin D, naringenin, chrysophanol, genistein and orobol. In total, 52 core targets were identified, including AKT serine/threonine kinase 1 (AKT1), tumor necrosis factor (TNF), B-cell lymphoma-2 (BCL2), serum albumin (ALB), and estrogen receptor 1 (ESR1). Gene ontology (GO) enrichment analysis identified 2331 entries related to biological processes, 98 entries associated with cellular components, and 203 entries linked to molecular functions. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis yielded 149 pathways, including those involved in EGFR tyrosine kinase inhibitor resistance, endocrine resistance, and the PI3K-Akt signaling pathway. Molecular docking results showed strong binding effects between the main active components and the core targets, with binding energies less than -5 kcal/mol. In summary, this study preliminarily elucidated the underlying mechanisms by which Flemingia philippinensis, through a multi-component, multi-target, and multi-pathway approach, ameliorates inflammation. This provides a theoretical foundation for the subsequent application of Flemingia philippinensis in inflammation amelioration.

Structural basis for hormone recognition and distinctive Gq protein coupling by the kisspeptin receptor.

Kisspeptin signaling through its G protein-coupled receptor, KISS1R, plays an indispensable role in regulating reproduction via the hypothalamic-pituitary-gonadal axis. Dysregulation of this pathway underlies severe disorders like infertility and precocious puberty. Here, we present cryo-EM structures of KISS1R bound to the endogenous agonist kisspeptin-10 and a synthetic analog TAK-448. These structures reveal pivotal interactions between peptide ligands and KISS1R extracellular loops for receptor activation. Both peptides exhibit a conserved binding mode, unveiling their common activation mechanism. Intriguingly, KISS1R displays a distinct 40° angular deviation in its intracellular TM6 region compared to other Gq-coupled receptors, enabling distinct interactions with Gq. This study reveals the molecular intricacies governing ligand binding and activation of KISS1R, while highlighting its exceptional ability to couple with Gq. Our findings pave the way for structure-guided design of therapeutics targeting this physiologically indispensable receptor.

Gallic Acid Can Promote Low-Density Lipoprotein Uptake in HepG2 Cells via Increasing Low-Density Lipoprotein Receptor Accumulation.

Gallic acid (GA) is a type of polyphenolic compound that can be found in a range of fruits, vegetables, and tea. Although it has been confirmed it improves non-alcoholic fatty liver disease (NAFLD), it is still unknown whether GA can improve the occurrence of NAFLD by increasing the low-density lipoprotein receptor (LDLR) accumulation and alleviating cholesterol metabolism disorders. Therefore, the present study explored the effect of GA on LDLR and its mechanism of action. The findings indicated that the increase in LDLR accumulation in HepG2 cells induced by GA was associated with the stimulation of the epidermal growth factor receptor-extracellular regulated protein kinase (EGFR-ERK1/2) signaling pathway. When the pathway was inhibited by EGFR mab cetuximab, it was observed that the activation of the EGFR-ERK1/2 signaling pathway induced by GA was also blocked. At the same time, the accumulation of LDLR protein and the uptake of LDL were also suppressed. Additionally, GA can also promote the accumulation of forkhead box O3 (FOXO3) and suppress the accumulation of hepatocyte nuclear factor-1α (HNF1α), leading to the inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) mRNA expression and protein accumulation. This ultimately results in increased LDLR protein accumulation and enhanced uptake of LDL in cells. In summary, the present study revealed the potential mechanism of GA's role in ameliorating NAFLD, with a view of providing a theoretical basis for the dietary supplementation of GA.

High-throughput proteomic analysis of extracellular vesicles from saliva by chemical probe-based array.

Extracellular vesicles (EVs) are cell-released, nucleus-free particles with a double-membrane structure that effectively prevents degradation of internal components by a variety of salivary enzymes. Saliva is an easily accessible biofluid that contains a wealth of valuable information for disease diagnosis and monitoring and especially reflect respiratory and digestive tract diseases. However, the lack of efficient and high-throughput methods for proteomic analysis of salivary biomarkers poses a significant challenge. Herein, we designed a salivary EV amphiphile-dendrimer supramolecular probe (SEASP) array which enables efficient enrichment and in situ detection of EVs protein biomarkers. Detergent Tween-20 washing of SEASP arrays removes high abundance of heteroproteins from saliva well. This array shows good analytical performance in the linear range of 10 µL-150 µL (LOD = 0.4 µg protein, or 10 µL saliva), exhibiting a good recovery (80.0 %). Compared to ultracentrifugation (UC), this procedure provides simple and convenient access to high-purity EVs (1.3 × 109 particles per mg protein) with good physiological status and structure. Coupling with mass spectrometry based proteomic analysis, differentially expressed proteins as selected asthma biomarkers have been screened. Then, we validated the proteomics primary screening results through clinical samples (100 µL each) using the SEASP array. Utilizing the dual antibody fluorescence technology, SEASP enables the simultaneous high-throughput detection of two proteins. Therefore, the EVs marker protein CD81 could be used as an internal standard to normalize the number of EVs, which was stably expressed in EVs. Proteomics and array results suggested that HNRNPU (P = 4.9 * 10-6) and MUC5B (P = 4.7 * 10-11) are promising protein biomarkers for infantile asthma. HNRNPU and MUC5B may be associated with disease onset and subtypes. The SEASP arrays provide a significant advancement in the field of salivary biomarker. The array enables high-throughput in situ protein detection for highly viscous and complex biological samples. It provides a rapid, low-cost, highly specific screening procedure and experimental basis for early disease screening and diagnosis in the field of liquid biopsy.

Batch Specular Plane Flatness Measurements Based on Phase Measuring Deflectometry.

Flatness is a critical parameter in the manufacturing industry, directly impacting the fit and overall product performance. As the efficiency of manufacturing continues to advance, there is an increasing demand for more accurate and efficient measurement techniques. Existing methods often struggle to strike a balance between precision and efficiency. In response, this article introduces a novel approach that is capable of achieving high-precision and rapid measurements concerning multiple surfaces. By enhancing the traditional phase measuring deflectometry (PMD) method, employing a matching technique based on polar lines and normal vector constraints to address discrete surface measurement challenges, and implementing a plane pre-positioning method to tackle low efficiency in binocular matching and solving, we successfully performed swift and synchronized measurements for a large batch of specular surfaces and obtained the three-dimensional surface profile of each measured surface. Through experimental validation, the method proposed in this paper can perform the batch measurement of specular planes while maintaining high measurement accuracy.

Identification of a 5-Gene Cuproptosis Signature Predicting the Prognosis for Colon Adenocarcinoma Based on WGCNA.

Background: Colorectal cancer is a highly aggressive malignant tumor that primarily affects the digestive system. It is frequently diagnosed at an advanced stage. Cuproptosis is a copper-dependent form cell death mechanism, distinct from all other known pathways underlying cell death, tumor progression, prognosis, and immune response. Although the role of cuproptosis in colorectal cancer has been investigated over time, there is still an urgent need to explore new methods and insights to understand its potential function. Methods: The Gene Expression Omnibus and The Cancer Genome Atlas gene expression data were systematically explored to investigate the role of cuproptosis in colon adenocarcinoma. The weighted gene coexpression network analysis was used to construct a gene coexpression network and identify the critical module and cuproptosis-related genes correlated with colon adenocarcinoma prognosis. A cuproptosis-related genes prognostic signature for colon adenocarcinoma was identified and validated. To validate the identified gene signature, quantitative reverse transcription-polymerase chain reaction was performed. Cell proliferation assays were analyzed by CCK8 and cell cycle detection. In addition, reactive oxygen species assay was also analyzed. Results: Five hub cuproptosis-related genes (Dihydrolipoamide S-acetyltransferase, Cyclin-dependent kinase inhibitor 2A, ATOX1, VEGFA, and ULK1) were screened and a prognostic risk model for predicting overall survival was established based on these genes. The model was successfully tested in the validation cohort and the GEPIA database. Colon adenocarcinoma patients were categorized into high-risk and low-risk groups based on risk scores. The study revealed that patients with higher risk scores were more likely to have a poor prognosis. Moreover, Dihydrolipoamide S-acetyltransferase was a tumor suppressor gene that can induce cell death and affected the redox reactions in the colon cancer cell line. Conclusions: These findings suggest that the newly identified 5-gene signature may serve as a more reliable prognostic factor than clinical factors such as age and stage of disease. These findings offer a theoretical foundation for further investigation into potential cuproptosis-related biomarkers for predicting colon adenocarcinoma prognosis in the future.

Evolution of H7N9 highly pathogenic avian influenza virus in the context of vaccination.

Human infections with the H7N9 influenza virus have been eliminated in China through vaccination of poultry; however, the H7N9 virus has not yet been eradicated from poultry. Carefully analysis of H7N9 viruses in poultry that have sub-optimal immunity may provide a unique opportunity to witness the evolution of highly pathogenic avian influenza virus in the context of vaccination. Between January 2020 and June 2023, we isolated 16 H7N9 viruses from samples we collected during surveillance and samples that were sent to us for disease diagnosis. Genetic analysis indicated that these viruses belonged to a single genotype previously detected in poultry. Antigenic analysis indicated that 12 of the 16 viruses were antigenically close to the H7-Re4 vaccine virus that has been used since January 2022, and the other four viruses showed reduced reactivity with the vaccine. Animal studies indicated that all 16 viruses were nonlethal in mice, and four of six viruses showed reduced virulence in chickens upon intranasally inoculation. Importantly, the H7N9 viruses detected in this study exclusively bound to the avian-type receptors, having lost the capacity to bind to human-type receptors. Our study shows that vaccination slows the evolution of H7N9 virus by preventing its reassortment with other viruses and eliminates a harmful characteristic of H7N9 virus, namely its ability to bind to human-type receptors.

Ethanol as Solvent Additives with Competitive Effect for High-Stable Aqueous Zinc Batteries.

Aqueous zinc-ion batteries are emerging as promising sustainable energy-storage devices. However, their cyclic stability is still a great challenge due to the inevitable parasitic reaction and dendrite growth induced by water. Herein, a cosolvent strategy based on competitive effect is proposed to address the aforementioned challenges. Ethanol with a higher Gutmann donor number demonstrates lower polarity and better wettability on the Zn surface compared with water, which endows ethanol with the ability of minimizing water activity by weakening H bonds and preferentially adsorbing on the Zn electrode. The above competitive advantages synergistically contribute to inhibiting the decomposition of free water and dendrite growth. Besides, an organic-inorganic hybrid solid-electrolyte interphase layer is in situ built based on ethanol additives, where organic matrix suppresses water corrosion while inorganic fillers promote fast Zn2+ diffusion. Consequently, the electrolyte with ethanol additives boosts a high reversibility of Zn deposition, long-term durability, as well as superior Zn2+ diffusibility in both Zn half-cells (Zn||Cu and Zn||Zn batteries) and Zn full cells (Zn||PTCDA and Zn||VO2 batteries). This work sheds light on a universal strategy to design a high-reversible and dendrite-free Zn anode for stable aqueous batteries.

Exercise promotes osteogenic differentiation by activating the long non-coding RNA H19/microRNA-149 axis.

BACKGROUND: Regular physical activity during childhood and adolescence is beneficial to bone development, as evidenced by the ability to increase bone density and peak bone mass by promoting bone formation. AIM: To investigate the effects of exercise on bone formation in growing mice and to investigate the underlying mechanisms. METHODS: 20 growing mice were randomly divided into two groups: Con group (control group, n = 10) and Ex group (treadmill exercise group, n = 10). Hematoxylin-eosin staining, immunohistochemistry, and micro-CT scanning were used to assess the bone formation-related indexes of the mouse femur. Bioinformatics analysis was used to find potential miRNAs targets of long non-coding RNA H19 (lncRNA H19). RT-qPCR and Western Blot were used to confirm potential miRNA target genes of lncRNA H19 and the role of lncRNA H19 in promoting osteogenic differentiation. RESULTS: Compared with the Con group, the expression of bone morphogenetic protein 2 was also significantly increased. The micro-CT results showed that 8 wk moderate-intensity treadmill exercise significantly increased bone mineral density, bone volume fraction, and the number of trabeculae, and decreased trabecular segregation in the femur of mice. Inhibition of lncRNA H19 significantly upregulated the expression of miR-149 and suppressed the expression of markers of osteogenic differentiation. In addition, knockdown of lncRNA H19 significantly downregulated the expression of autophagy markers, which is consistent with the results of autophagy-related protein changes detected in mouse femurs by immunofluorescence. CONCLUSION: Appropriate treadmill exercise can effectively stimulate bone formation and promote the increase of bone density and bone volume in growing mice, thus enhancing the peak bone mass of mice. The lncRNA H19/miR-149 axis plays an important regulatory role in osteogenic differentiation.

Precise synthesis of BN embedded perylene diimide oligomers for fast-charging and long-life potassium-organic batteries.

Replacing the C[double bond, length as m-dash]C bond with an isoelectronic BN unit is an effective strategy to tune the optoelectronic properties of polycyclic aromatic hydrocarbons (PAHs). However, precise control of the BN orientations in large PAH systems is still a synthetic challenge. Herein, we demonstrate a facile approach for the synthesis of BN embedded perylene diimide (PDI) nanoribbons, and the polarization orientations of the BN unit were precisely regulated in the two PDI trimers. These BN doped PDI oligomers show great potential as organic cathodes for potassium-ion batteries (PIBs). In particular, trans-PTCDI3BN exhibits great improvement in voltage potential, reversible capacities (ca. 130 mA h g-1), superior rate performance (19 s to 69% of the maximum capacity) and ultralong cyclic stability (nearly no capacity decay over 30 000 cycles), which are among those of state-of-the-art organic-based cathodes. Our synthetic approach stands as an effective way to access large PAHs with precisely controlled BN orientations, and the BN doping strategy provides useful insight into the development of organic electrode materials for secondary batteries.

The luxS deletion reduces the spoilage ability of Shewanella putrefaciens: An analysis focusing on quorum sensing and activated methyl cycle.

The luxS mutant strains of Shewanella putrefaciens (SHP) were constructed to investigate the regulations of gene luxS in spoilage ability. The potential regulations of AI-2 quorum sensing (QS) system and activated methyl cycle (AMC) were studied by analyzing the supplementation roles of key circulating substances mediated via luxS, including S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), methionine (Met), homocysteine (Hcy) and 4,5-dihydroxy-2,3-pentanedione (DPD). Growth experiments revealed that the luxS deletion led to certain growth limitations of SHP, which were associated with culture medium and exogenous additives. Meanwhile, the decreased biofilm formation and diminished hydrogen sulfide (H2S) production capacity of SHP were observed after luxS deletion. The relatively lower total volatile base nitrogen (TVB-N) contents and higher sensory scores of fish homogenate with luxS mutant strain inoculation also indicated the weaker spoilage-inducing effects after luxS deletion. However, these deficiencies could be offset with the exogenous supply of circulating substances mentioned above. Our findings suggested that the luxS deletion would reduce the spoilage ability of SHP, which was potentially attributed to the disorder of AMC and AI-2 QS system.

Prevalence and Associated Factors of Atherosclerotic Plaque and Stenosis in Renal Arteries: A Community-Based Study.

The epidemiology of renal artery atherosclerosis in community populations is poorly documented. This study aimed to determine the prevalence of renal artery plaque (RAP) and atherosclerotic renal artery stenosis (ARAS), and the association of plaque and stenosis with vascular risk factors and kidney disease markers among community-dwelling adults. We conducted a cross-sectional analysis of the Polyvascular Evaluation for Cognitive Impairment and Vascular Events (PRECISE) study. RAP and ARAS were evaluated by thoracoabdominal computed tomography angiography. A total of 3045 adults aged 50-75 years were included. The prevalence of RAP and ARAS was 28.7% and 4.8%, respectively. The prevalence of RAP and ARAS was 41.3% and 7.7% in individuals aged ≥60 years, 42.9% and 8.7% in hypertensives, and 45.4% and 8.5% in individuals with chronic kidney disease. Older age, hypertension, higher total cholesterol level, and lower high-density lipoprotein cholesterol level were independently associated with RAP and ARAS. A higher urinary albumin-creatinine ratio was independently associated with RAP, whereas a reduced estimated glomerular filtration rate was independently associated with ARAS. In conclusion, there was a non-negligible prevalence of RAP and ARAS among the older, community population in China.

The association between new inflammation markers and frequent peritoneal dialysis-associated peritonitis.

OBJECTIVE: To validate an association between new inflammation and frequent peritoneal dialysis-associated peritonitis (PDAP). MATERIALS AND METHODS: In China, retrospective clinical data were collected on 208 patients who received continuous ambulatory peritoneal dialysis (CAPD) between 2010 and 2021. The patients were divided into two groups: non-frequent PDAP (the interval between two peritonitis episodes of more than one year) and frequent PDAP (the interval between two peritonitis episodes of less than one year). Patients with their first episode of peritonitis had their age, gender, history of hypertension, diabetic disease, underlying renal disease, bacterial infection, and laboratory data collected. The outcomes of bacterial dispersion, systemic immune-inflammation index (SII), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), and risk variables associated with frequent PDAP were analyzed. RESULTS: There are differences between the two groups in dialysis time (p = 0.006), hypertensive nephropathy (p = 0.038), staphylococcus (p = 0.035), white blood cells (p = 0.001), neutrophil (p < 0.01), lymphocyte (p < 0.01), platelet(p = 0.01), SII(p < 0.01), CRP/HDL-C (p = 0.002), CRP (p < 0.001), serum creatinine (p = 0.007), blood urea nitrogen (p = 0.05), serum magnesium (0.03), serum potassium (p = 0.007), and dialysate polymorphonuclear cells (p = 0.004). Multifactorial logistic regression analysis found that SII (p < 0.001), CRP/HDL-C (p = 0.041), and Diabetes mellitus (p = 0.027) were independent risk factors for frequent PDAP. The ROC curve analysis revealed that combining SII with CRP/HDL-C resulted in the largest AUC area (AUC = 0.814). CONCLUSIONS: Our findings offer clinical proof of the combination of SII and CRP/HDL-C in patients with frequent PDAP.

Edaravone dexborneol alleviates ischemic injury and neuroinflammation by modulating microglial and astrocyte polarization while inhibiting leukocyte infiltration.

Poststroke inflammation is essential in the mechanism of secondary injury, and it is orchestrated by resident microglia, astrocytes, and circulating immune cells. Edaravone dexborneol (EDB) is a combination of edaravone and borneol that has been identified as a clinical protectant for stroke management. In this study, we verified the anti-inflammatory effect of EDB in the mouse model of ischemia and investigated its modulatory action on inflammation-related cells. C57BL/6 male mice, which had the transient middle cerebral artery occlusion (tMCAO), were treated (i.p.) with EDB (15 mg/kg). EDB administration significantly reduced the brain infarction and improved the sensorimotor function after stroke. And EDB alleviated the neuroinflammation by restraining the polarization of microglia/macrophages and astrocyte toward proinflammatory phenotype and inhibiting the production of proinflammatory cytokines (such as IL-1ß, TNF-α, and IL-6) and chemokines (including MCP-1 and CXCL1). Furthermore, EDB ameliorated the MCAO-induced impairment of Blood-brain barrier (BBB) by suppressing the degradation of tight junction protein and attenuated the accumulation of peripheral leukocytes in the ischemic brain. Additionally, systemic EDB administration inhibited the macrophage phenotypic shift toward the M1 phenotype and the macrophage-dependent inflammatory response in the spleen and blood. Collectively, EDB protects against ischemic stroke injury by inhibiting the proinflammatory activation of microglia/macrophages and astrocytes and through reduction by invasion of circulating immune cells, which reduces central and peripheral inflammation following stroke.

Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM.

RNA sequencing and genetic data support spleen tyrosine kinase (SYK) and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) as putative targets to be modulated for Alzheimer's disease (AD) therapy. FCER1G is a component of Fc receptor complexes that contain an immunoreceptor tyrosine-based activation motif (ITAM). SYK interacts with the Fc receptor by binding to doubly phosphorylated ITAM (p-ITAM) via its two tandem SH2 domains (SYK-tSH2). Interaction of the FCER1G p-ITAM with SYK-tSH2 enables SYK activation via phosphorylation. Since SYK activation is reported to exacerbate AD pathology, we hypothesized that disruption of this interaction would be beneficial for AD patients. Herein, we developed biochemical and biophysical assays to enable the discovery of small molecules that perturb the interaction between the FCER1G p-ITAM and SYK-tSH2. We identified two distinct chemotypes using a high-throughput screen (HTS) and orthogonally assessed their binding. Both chemotypes covalently modify SYK-tSH2 and inhibit its interaction with FCER1G p-ITAM, however, these compounds lack selectivity and this limits their utility as chemical tools.