Inhibition of TREM-1 alleviates neuroinflammation by modulating microglial polarization via SYK/p38MAPK signaling pathway after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI), as a major public health problem, is characterized by high incidence rate, disability rate, and mortality rate. Neuroinflammation plays a crucial role in the pathogenesis of TBI. Triggering receptor expressed on myeloid cells-1 (TREM-1) is recognized as an amplifier of the inflammation in diseases of the central nervous system (CNS). However, the function of TREM-1 remains unclear post-TBI. This study aimed to investigate the function of TREM-1 in neuroinflammation induced by TBI. METHODS: Brain water content (BWC), modified neurological severity score (mNSS), and Morris Water Maze (MWM) were measured to evaluate the effect of TREM-1 inhibition on nervous system function and outcome after TBI. TREM-1 expression in vivo was evaluated by Western blotting. The cellular localization of TREM-1 in the damaged region was observed via immunofluorescence staining. We also conducted Western blotting to examine expression of SYK, p-SYK and other downstream proteins. RESULTS: We found that inhibition of TREM-1 reduced brain edema, decreased mNSS and improved neurobehavioral outcomes after TBI. It was further determined that TREM-1 was expressed on microglia and modulated subtype transition of microglia. Inhibition of TREM-1 alleviated neuroinflammation, which was associated with SYK/p38MAPK signaling pathway. CONCLUSIONS: These findings suggest that TREM-1 can be a potential clinical therapeutic target for alleviating neuroinflammation after TBI.

High stocking rates effects in continuous season long grazing reduces the contribution of microbial necromass to soil organic carbon in a semi-arid grassland in Inner Mongolia.

Livestock grazing strongly influences the accumulation of soil organic carbon (SOC) in grasslands. However, whether the changes occurring in SOC content under different intensities of continuous summer long grazing are associated with the changes in microbially-derived necromass C remains unclear. Here, we established a sheep grazing experiment in northern China in 2004 with four different stocking rates. Soil samples were collected after 17 years of grazing and analyzed for physical, chemical, and microbial characteristics. Grazing decreased SOC and microbial necromass carbon (MNC). Notably, grazing also diminished contributions of MNC to SOC. MNC declined with decreasing plant carbon inputs with degradation of the soil environment. Direct reductions in microbial necromass C, which indirectly reduced SOC, resulted from reduced in plant C inputs and microbial abundance and diversity. Our study highlights the key role of stocking rate in governing microbial necromass C and SOC and the complex relationships these variables.

Fibroblast growth factor 21 mitigates lupus nephritis progression via the FGF21/Irgm 1/NLRP3 inflammasome pathway.

As an endocrine cytokine, fibroblast growth factor 21 (FGF21) exhibits anti-inflammatory properties. With the development of lupus nephritis (LN), which is tightly related to pathogenic factors, including inflammation and immune cell dysregulation, we explored the impact of Fibroblast Growth Factor 21 (FGF21) as well as its underlying mechanism. We induced an in vivo LN model using pristane in both wild-type C57BL/6 and FGF21 knockout (FGF21-/-) mice. LN serum obtained from 32-week-old wild-type LN mice was used to stimulate RAW264.7 and human renal tubular epithelial (HK-2) cells to mimic an in vitro LN model. Moreover, our findings revealed that FGF21-/- mice showed more severe kidney injury compared to wild-type mice, as evidenced by increased levels of renal function markers, inflammatory factors, and fibrosis markers. Notably, exogenous administration of FGF21 to wild-type LN mice markedly mitigated these adverse effects. Additionally, we used tandem mass tag (TMT)-based quantitative proteomics to detect differentially expressed proteins following FGF21 treatment. Results indicated that 121 differentially expressed proteins influenced by FGF21 were involved in biological processes such as immune response and complement activation. Significantly upregulated protein Irgm 1, coupled with modulated inflammatory response, appeared to contribute to the beneficial effects of FGF21. Furthermore, Western blot analysis demonstrated that FGF21 upregulated Irgm 1 while inhibiting nucleotide-binding oligomerization domain-like receptors family pyrin domain including 3 (NLRP3) inflammasome expression. Silencing Irgm 1, in turn, reversed FGF21's inhibitory effect on NLRP3 inflammasome. In summary, FGF21 can potentially alleviate pristane-induced lupus nephritis in mice, possibly through the FGF21/Irgm 1/NLRP3 inflammasome pathway.

Multi-Omics Approach Reveals OsPIL1 as a Regulator Promotes Rice Growth, Grain Development, and Blast Resistance.

Rice (Oryza sativa) is a crucial crop, achieving high yield concurrent pathogen resistance remains a challenge. Transcription factors play roles in growth and abiotic tolerance. However, rice phytochrome-interacting factor-like 1 (OsPIL1) in pathogen resistance and agronomic traits remains unexplored. We generated OsPIL1 overexpressing (OsPIL1 OE) rice lines and evaluated their impact on growth, grain development, and resistance to Magnaporthe oryzae. Multiomics analysis (RNA-seq, metabolomics, and CUT&Tag) and RT-qPCR validated OsPIL1 target genes and key metabolites. In the results, OsPIL1 OE rice lines exhibited robust growth, longer grains, and enhanced resistance to M. oryzae without compromising growth. Integrative multiomics analysis revealed a coordinated regulatory network centered on OsPIL1, explaining these desirable traits. OsPIL1 likely acts as a positive regulator, targeting transcriptional elements or specific genes with direct functions in several biological programs. In particular, a range of key signaling genes (phosphatases, kinases, plant hormone genes, transcription factors), and metabolites (linolenic acid, vitamin E, trigonelline, d-glucose, serotonin, choline, genistein, riboflavin) contributed to enhanced rice growth, grain size, pathogen resistance, or a combination of these traits. These findings highlight OsPIL1's regulatory role in promoting important traits and provide insights into potential strategies for rice breeding.

A mechanical and three-dimensional finite element study of the optimum tooth sectioning depth during the extraction of low-level horizontally impacted mandibular third molar.

The present study aims to determine the optimum sectioning depth for the extraction of low-level horizontally impacted mandibular third molar (LHIM3M) using mechanical and finite element analysis. One hundred and fifty extracted mandibular third molars were randomly divided into three groups: 1, 2 or 3 mm of tooth tissue was retained at the bottom of the crown. The breaking force of teeth was tested in a universal strength testing machine. The fracture surface was observed and the type of tooth breakage was recorded. According to the three groups, corresponding 3D finite element models were created. The breaking force obtained in the mechanical study was, respectively, applied and the stress and strain of the teeth and surrounding tissues were analysed. Breaking force decreased as sectioning depth increased. The 2 mm group produced the lowest rate of incomplete breakage (10%). In the 2 mm model, the stresses were evenly distributed in the tooth tissue at the bottom of the fissure, and the maximal stress was located in the tissue close to the root segment. The maximum values of stresses in the bone and of strains in the periodontal ligament of the second molar and bone were lower in the 1 mm model than in other models. Their distribution was similar in the three models. A sectioning depth of 1 mm group saves labour during the extraction of LHIM3M, compared to 2 and 3 mm; 2 mm might be the appropriate sectioning depth in terms of breakage shapes.

Comparison of errors in ablation depth calculation after myopic femtosecond laser in situ keratomileusis in patients with different degrees of myopia: a prospective study.

BACKGROUND: To investigate the difference between the predicted preoperative corneal ablation depth and the measured ablation depth for femtosecond laser in situ keratomileusis (FS-LASIK) in patients with different degrees of myopia, and to analyze the source of the difference. METHODS: A total of 55 patients (109 eyes) were included in this study. Multiple logistics regression was applied to analyze the sources affecting postoperative refractive outcomes. The difference between the preoperative predicted corneal ablation depth and the 1-day postoperative ablation depth in patients with different degrees of myopia was explored using linear regression. Corneal biomechanical parameters influencing error in ablation depth calculation were examined using multiple linear regression. RESULTS: One hundred and nine eyes were divided into low to moderate myopia (55 eyes, myopia of 6 D or less), high myopia (45 eyes, myopia ranging from 6 D to a maximum of 9 D), and very high myopia group (9 eyes, myopia greater than 9 D) based on preoperative refractive error (spherical equivalent). Postoperative visual outcomes were comparable among the three groups of patients, with no significant difference in uncorrected visual acuity (UCVA). We did find notable disparities in spherical equivalent (SE) and central corneal thickness (CCT) in patients with different degrees of myopia at 1 day postoperatively (all p < 0.001). Logistic regression analysis showed that error in ablation depth calculation was an independent risk factor for refractive outcomes one day after surgery (OR = 1.689, 95% CI: 1.366 - 2.089). There was a substantial discrepancy in error in ablation depth calculation at 1 day postoperatively between the three groups. The measured ablation depth of the laser platform was lower than the predicted ablation depth in the low to moderate myopia and very high myopia groups, but the opposite was true in the high myopia group. Pre-operative SE (p < 0.001) and corneal front minimum radius of curvature (Front Rmin) (p = 0.007) obviously influenced the error in ablation depth calculation. CONCLUSIONS: Error in ablation depth calculation values vary significantly between patients with different degrees of myopia and correlate highly with preoperative SE and Front Rmin. At the same time, the available evidence suggests that error in ablation depth calculation is an influential factor in postoperative refractive status, so it is imperative to control error in ablation depth calculation.

Rapid ultra-sensitive nucleic acid detection using plasmonic fiber-optic spectral combs and gold nanoparticle-tagged targets.

Nucleic acid (NA) is a widely-used biomarker for viruses. Accurate quantification of NA can provide a reliable basis for point-of-care diagnosis and treatment. Here, we propose a tilted fiber Bragg grating (TFBG)-based plasmonic fiber-optic spectral comb for fast response and ultralow limit NA detection. The TFBG is coated with a gold film which enables excitation of surface plasmon resonance (SPR), and single-stranded probe NAs with known base sequences are assembled on the gold film. To enhance sensitivity of refractive index (RI) for sensing a chosen combination of probe and target NAs around the TFBG surface, gold nanoparticles (AuNPs) are bonded to the target NA molecules as "RI-labels". The NA combination-induced aggregation of AuNPs induces significant spectral responses in the TFBG that would be below the detection threshold for the NAs in the absence of the AuNPs. The proposed TFBG-SPR NA sensor shows a fast response time of 30 s and an ultra-wide NA detection range from 1 × 10-18 mol/L to 1 × 10-7 mol/L. In the NA concentration range of 1 × 10-12 mol/L (1 pM) to 105 pM, an ultra-high sensitivity of 1.534 dB/lg(pM) is obtained. The sensor achieves an ultra-low limit of detection down to 1.0 × 10-18 mol/L (1 aM), which is more than an order of magnitude lower than the previous reports. The proposed sensor not only shows potentials in practical applications of NA detection, but also provides a new way for TFBG-SPR biochemical sensors to achieve higher RI sensitivity.

Anisotropic ductility and thermoelectricity of van der Waals GeAs.

Wearable thermoelectric applications require materials with both high energy conversion efficiency and excellent flexibility/deformability. Inorganic thermoelectric materials have shown high conversion efficiency, but they are usually brittle and have poor mechanical flexibility, which makes their integration into flexible devices a challenging task. GeAs is a group IV-V binary compound with a van der Waals layered structure, and its thermoelectric response has been reported. Herein, we investigate the mechanical and thermoelectric properties of GeAs crystal by a combination of density functional theory and density functional perturbation theory methods. Our results show that GeAs features a moderately dispersive valence band and multivalley convergence, which give rise to a large Seebeck coefficient and power factor when it is properly p-doped. Remarkably, its electrical transport in the out-of-plane direction even outperforms that in the in-plane direction, while phonon transport is suppressed, leading to a predominant thermoelectric response in the vertical direction. More interestingly, GeAs demonstrates a structural stiffness higher than thermoelectric CuInTe2 and PbTe, and a ductility ratio comparable to a recently discovered plastic semiconductor, InSe. The stress-strain curve simulation reveals that GeAs can withstand deformations up to 20%. These findings showcase GeAs as a ductile thermoelectric material suitable for wearable devices and energy conversion.

Multiple roles of LncRNA-BMNCR on cell proliferation and apoptosis by targeting miR-145/CBFB axis in BMECs.

Bovine mastitis is one of the most serious and costly disease affecting dairy cattle production. The present study explored the inflammatory response and autoprotective mechanism of a novel specific high expression BMNCR (bovine mastitis related long non-coding RNA) in S. aureus induced mastitis by miR-145/CBFB axis in dairy cows from the perspective of molecular genetics. In bovine mammary epithelial cells, we preformed loss of function experiments to detect changes in cytokine, proliferation and apoptosis by qRT-PCR, western blot, flow cytometry and EdU staining. The results demonstrated that BMNCR significantly increased cell apoptosis, and inhibited cell proliferation. However, the secretion of IL-1α, IL-2, IL-6, IL-8 and IL-12 were enhanced after knock-down BMNCR. Bioinformatics analysis demonstrated that BMNCR could target 8 miRNAs, in-depth analyses indicated that BMNCR acts as a molecular sponge for bta-miR-145 and CBFB was one of 23 target gene of bta-miR-145 . The results of the present study demonstrated that the role of BMNCR in S. aureus induced mastitis can be mediated by sponge bta-miR-145 activating CBFB expression. BMNCR could be a potential target for mastitis diagnosis and therapy, which may enrich the theoretical research of therapeutic intervention, and further increase milk yield and improve milk quality.

Exogenous Jasmonic Acid Alleviates Blast Resistance Reduction Caused by LOX3 Knockout in Rice.

Lipoxygenase 3 (LOX3) is a lipid peroxidase found in rice embryos that is known to affect seed quality. Interestingly, deletion of the LOX3 gene has been shown to improve rice seed quality but decrease resistance to rice blast disease and drought. To investigate these opposing effects, we generated a LOX3 knockout construct (ΔLox3) in rice (Oryza sativa L.) plants. Blast resistance and transcription levels of rice genes in ΔLox3 rice plants and the effects of exogenous jasmonic acid (JA) on resistance and transcriptional levels of rice genes in Magnaporthe oryzae-infected ΔLox3 rice plants were further elucidated. The results showed that the ΔLox3 plants exhibited normal phenotypes, with high levels of methyl-linolenate and reactive oxygen species (ROS), and the genes involved in three Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways contributed to rice seed quality. M. oryzae-infected ΔLox3 plants exhibited serious blast symptoms with a reduced defense response but increased ROS-mediated cell death, and the genes involved in seven KEGG pathways contributed to rice seed quality. Exogenous JA treatment alleviated blast symptoms in infected ΔLox3 plants by hindering hyphal expansion, inhibiting ROS-mediated cell death, and increasing the defense response, and genes involved in 12 KEGG pathways contributed to rice seed quality. These findings demonstrate that LOX3 plays an important role in rice growth and defense, and its knockout improves rice quality at the expense of disease resistance. Exogenous JA provides a means to compensate for the reduction in defense responses of LOX3 knockout rice lines, suggesting potential applications in agricultural production.

Dendrimer-conjugated isotretinoin for controlled transdermal drug delivery.

BACKGROUND: In the present study, we aimed to develop a novel isotretinoin delivery model for treating skin diseases, revealing its potential advantages in drug delivery and targeted therapy. Using a self-assembly strategy, we grafted a dendrimer, based on a well-defined branched structure for nanomedical devices, with a well-defined nanoarchitecture, yielding spherical, highly homogeneous molecules with multiple surface functionalities. Accordingly, a self-assembled dendrimer-conjugated system was developed to achieve the transdermal delivery of isotretinoin (13cRA-D). RESULTS: Herein, 13cRA-D showed remarkable controlled release, characterized by slow release in normal tissues but accelerated release in tissues with low pH, such as sites of inflammation. These release characteristics could abrogate the nonteratogenic side effects of isotretinoin and allow efficient skin permeation. Moreover, 13cRA-D exhibited high therapeutic efficacy in acne models. Based on in vitro and in vivo experimental results, 13cRA-D afforded better skin penetration than isotretinoin and allowed lesion targeting. Additionally, 13cRA-D induced minimal skin irritation. CONCLUSION: Our findings suggest that 13cRA-D is a safe and effective isotretinoin formulation for treating patients with skin disorders.

Glycyrrhizic Acid Protects Glomerular Podocytes Induced by High Glucose by Modulating SNARK/AMPK Signaling Pathway.

OBJECTIVE: Diabetic nephropathy is one of the most important microvascular complications of diabetes, which mainly refers to glomerular capillary sclerosis. Podocytes are an important part of glomerular capillaries. Previous clinical and basic studies have shown that fibrosis is the main factor of diabetic nephropathy. This study aimed to assess the protective mechanism of glycyrrhizic acid (GA) on glomerular podocytes induced by high glucose as we hypothesized that GA may have antifibrotic and anti-inflammatory effects on podocytes through regulation of the adenosine 5'-monophosphate-activated protein kinase (AMPK)/sucrose nonfermenting AMPK-related kinase (SNARK) signaling pathway. METHODS: SNARK siRNA was used to transfect podocytes. Real-time quantitative polymerase chain reaction and immunofluorescence staining assays were used for molecular and pathological analysis. The expression levels of key pathway proteins (including TGF-ß1, α-SMA, SITR1, AMPKα, LKB1, PGC-1α, NF-κB, IL-6, and TNF-α) were verified by Western blotting. The expression of inflammatory factors in podocytes was detected by ELISA. RESULTS: We demonstrated that GA decreased the expression of podocyte fibrosis signaling pathway-related factors by upregulating the AMPK pathway and its related factors. However, after transfection of podocytes with SNARK siRNA, there was an increased expression of fibrosis-related factors and inflammation-related factors. CONCLUSION: GA can protect podocytes and alleviate fibrosis and inflammation induced by high glucose, which is related to the AMPK signaling pathway. Meanwhile, knockdown of SNARK protein can inhibit the AMPK signaling pathway, aggravate fibrosis, and increase inflammation.

Structure-Activity Relationship Studies on Cell-Potent Nicotinamide N-Methyltransferase Bisubstrate Inhibitors.

Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme implicated in multiple diseases, making it a promising therapeutic target. Building upon our recently reported NNMT inhibitor II399, we systematically investigate the structure-activity relationship by designing and synthesizing a series of analogues. Among them, two top inhibitors II559 (Ki = 1.2 nM) and II802 (Ki = 1.6 nM) displayed over 5000-fold selectivity for NNMT over closely related methyltransferases. Moreover, II559 and II802 showed enhanced cellular inhibition, with a cellular IC50 value of approximately 150 nM, making them the most cell-potent bisubstrate inhibitors reported to date. Furthermore, both inhibitors reduced the cell viability with a GI50 value of ∼10 µM and suppressed the migration of aggressive clear cell renal cancer cell carcinoma cell lines. Overall, II559 and II802 would serve as valuable probes to investigate the enzymatic function of NNMT in health and diseases.

A Prototype Assay Multiplexing SARS-CoV-2 3CL-Protease and Angiotensin-Converting Enzyme 2 for Saliva-Based Diagnostics in COVID-19.

With the current state of COVID-19 changing from a pandemic to being more endemic, the priorities of diagnostics will likely vary from rapid detection to stratification for the treatment of the most vulnerable patients. Such patient stratification can be facilitated using multiple markers, including SARS-CoV-2-specific viral enzymes, like the 3CL protease, and viral-life-cycle-associated host proteins, such as ACE2. To enable future explorations, we have developed a fluorescent and Raman spectroscopic SARS-CoV-2 3CL protease assay that can be run sequentially with a fluorescent ACE2 activity measurement within the same sample. Our prototype assay functions well in saliva, enabling non-invasive sampling. ACE2 and 3CL protease activity can be run with minimal sample volumes in 30 min. To test the prototype, a small initial cohort of eight clinical samples was used to check if the assay could differentiate COVID-19-positive and -negative samples. Though these small clinical cohort samples did not reach statistical significance, results trended as expected. The high sensitivity of the assay also allowed the detection of a low-activity 3CL protease mutant.

Identification cloning and functional analysis of novel natural antisense lncRNA CFL1-AS1 in cattle.

Long noncoding RNAs have been identified as important regulators of gene expression and animal development. The expression of natural antisense transcripts (NATs) transcribed in the opposite direction to protein-coding genes is usually positively correlated with the expression of homologous sense genes and is the key factor for expression. Here, we identified a conserved noncoding antisense transcript, CFL1-AS1, that plays an important role in muscle growth and development. CFL1-AS1 overexpression and knockout vectors were constructed and transfected into 293T and C2C12 cells. CFL1-AS1 positively regulated CFL1 gene expression, and the expression of CFL2 was also downregulated when CFL1-AS1 was knocked down. CFL1-AS1 promoted cell proliferation, inhibited apoptosis and participated in autophagy. This study expands the research on NATs in cattle and lays a foundation for the study of the biological function of bovine CFL1 and its natural antisense chain transcript CFL1-AS1 in bovine skeletal muscle development. The discovery of this NAT can provide a reference for subsequent genetic breeding and data on the characteristics and functional mechanisms of NATs.

Anti-inflammatory and immunomodulatory effects of polysaccharide extracted from Wuguchong (maggot) on 2,4-dinitrochlorobenzene-induced atopic dermatitis in mice.

Atopic dermatitis (AD) is an inflammatory, heterogeneous, chronic skin disorder characterized by recurrent eczematous lesions and intense pruritus, and the pathophysiology mechanism of AD is known for immune dysregulation and inflammatory responses. Wuguchong (maggot) has been widely used in the wound field and found with pharmacological properties of the anti-inflammatory and immunomodulatory function. Recently, some polysaccharides were proven to have beneficial effects on AD skin lesions in mice and humans. However, the effect of the polysaccharide extracted from Wuguchong (PEW) on AD remains to be investigated. In the present study, we examined the anti-inflammatory and immunomodulatory effects of PEW on AD and explored the potential mechanisms. Balb/c mice were orally administrated with PEW to evaluate the therapeutic effect of PEW on 2,4-dinitrochlorobenzene (DNCB)-induced AD. Oral PEW administration significantly ameliorated the lesions and symptoms in AD mice, such as the ear thickness and ear swelling degree, epidermal and dermal thickness, and the infiltration of mast cells. In addition, PEW treatment decreased the levels of serum IgE and histamine, the frequencies of Th1 and Th17 cells, as well as the mRNA expression levels of Th1 and Th17 cytokines and nuclear transcript factors (IFN-γ, T-bet, IL-17A, and ROR-rt). Furthermore, the activation of the NF-κB pathway and the phosphorylation of MAPKs (p38, ERK, and JNK) were significantly suppressed by PEW treatment. Taken together, our study suggests that PEW exerts anti-inflammatory and immunomodulatory effects through inhibition of Th1 and Th17 responses and downregulation of NF-κB and MAPK pathways, PEW would be developed as a promising immune therapy for AD.