ABSTRACT
BACKGROUND: Sepsis is a life-threatening disease accompanied by disorders of the coagulation and immune systems. P2Y12 inhibitors, widely used for arterial thrombosis prevention and treatment, possess recently discovered anti-inflammatory properties, raising potential for improved sepsis prognosis. METHOD: We conducted a retrospective analysis using the data from Medical Information Mart for Intensive Care-IV database. Patients were divided into an aspirin-alone group versus a combination group based on the use of a P2Y12 inhibitor or not. Differences in 30-day mortality, length of stay (LOS) in intensive care unit (ICU), LOS in hospital, bleeding events and thrombotic events were compared between the two groups. RESULT: A total of 1701 pairs of matched patients were obtained by propensity score matching. We found that no statistically significant difference in 30-day mortality in aspirin-alone group and combination group (15.3% vs. 13.7%, log-rank p = 0.154). In addition, patients received P2Y12 inhibitors had a higher incidence of gastrointestinal bleeding (0.5% vs. 1.6%, p = 0.004) and ischemic stroke (1.7% vs. 2.9%, p = 0.023), despite having a shorter LOS in hospital (11.1 vs. 10.3, days, p = 0.043). Cox regression showed that P2Y12 inhibitor was not associated with 30-day mortality (HR = 1.14, 95% CI 0.95-1.36, p = 0.154). CONCLUSION: P2Y12 inhibitors did not provide a survival benefit for patients with sepsis 3 and even led to additional adverse clinical outcomes.
Subject(s)
Aspirin , Length of Stay , Propensity Score , Purinergic P2Y Receptor Antagonists , Sepsis , Humans , Male , Female , Sepsis/drug therapy , Sepsis/mortality , Aspirin/therapeutic use , Retrospective Studies , Aged , Middle Aged , Purinergic P2Y Receptor Antagonists/therapeutic use , Intensive Care Units , Treatment Outcome , Aged, 80 and over , Platelet Aggregation Inhibitors/therapeutic useABSTRACT
We describe the discovery of a thioester-containing glucocorticoid receptor modulator (GRM) payload and the corresponding antibody-drug conjugate (ADC). Payload 6 was designed for rapid hepatic inactivation to minimize systemic exposure of nonconjugated GRM. Mouse PK indicated that 6 is cleared 10-fold more rapidly than a first-generation GRM payload, resulting in 10-fold lower exposure and 3-fold decrease in Cmax. The anti-mTNF conjugate ADC5 fully inhibited inflammation in mouse contact hypersensitivity with minimal effects on corticosterone, a biomarker for systemic GRM effects, at doses up to and including 100 mg/kg. Concomitant inhibition of P1NP suggests potential delivery to cells involved in the remodeling of bone, which may be a consequence of TNF-targeting or bystander payload effects. Furthermore, ADC5 fully suppressed inflammation in collagen-induced arthritis mouse model after one 10 mg/kg dose for 21 days. The properties of the anti-hTNF conjugate were suitable for liquid formulation and may enable subcutaneous dosing.
Subject(s)
Arthritis, Experimental , Corticosterone , Immunoconjugates , Tumor Necrosis Factor-alpha , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/metabolism , Mice , Immunoconjugates/pharmacology , Immunoconjugates/chemistry , Immunoconjugates/pharmacokinetics , Immunoconjugates/therapeutic use , Corticosterone/blood , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Receptors, Glucocorticoid/metabolism , Receptors, Glucocorticoid/antagonists & inhibitors , Inflammation/drug therapy , Inflammation/metabolism , Glucocorticoids/pharmacology , Humans , Male , Disease Models, AnimalABSTRACT
Ustekinumab (UST), a fully human immunoglobulin G1 κ monoclonal antibody, exhibiting high affinity for the p40 subunit shared by IL-12 and IL-23, which play key roles in the pathogenesis of inflammatory bowel disease (IBD). By scaling the physiologically-based pharmacokinetic modeling (PBPK) model of UST in adult patients with IBD, we aim to predict effective dosages for UST in pediatric patients, thereby offering a more practical dosing regimen for real-world applications. In this work, a PBPK model for UST in adult patients with IBD has been developed using PK-Sim and Mobi. Advanced ontogeny model has been incorporated to extrapolate the model to pediatric patients. The simulation results showed that the fold errors of the predicted and observed values of the area under the curve (AUC) and peak plasma concentration (Cmax) were between 0.79 and 1.73. For children aged 6-18, it is recommended to administer the drug per kilogram of body weight, at the model-recommended dose, to achieve a median AUC similar to that of the adult reference population post-administration. This comprehensive model construction enables us to comprehensively and extensively explore the pharmacokinetic characteristics of UST in pediatric patients of different age groups, providing robust support for clinical applications and personalized drug therapy.
Subject(s)
Inflammatory Bowel Diseases , Models, Biological , Ustekinumab , Humans , Ustekinumab/pharmacokinetics , Ustekinumab/administration & dosage , Child , Adolescent , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/metabolism , Male , Female , Area Under Curve , Adult , Computer SimulationABSTRACT
JOURNAL/nrgr/04.03/01300535-202412000-00028/figure1/v/2024-04-08T165401Z/r/image-tiff Immune changes and inflammatory responses have been identified as central events in the pathological process of spinal cord injury. They can greatly affect nerve regeneration and functional recovery. However, there is still limited understanding of the peripheral immune inflammatory response in spinal cord injury. In this study, we obtained microRNA expression profiles from the peripheral blood of patients with spinal cord injury using high-throughput sequencing. We also obtained the mRNA expression profile of spinal cord injury patients from the Gene Expression Omnibus (GEO) database (GSE151371). We identified 54 differentially expressed microRNAs and 1656 differentially expressed genes using bioinformatics approaches. Functional enrichment analysis revealed that various common immune and inflammation-related signaling pathways, such as neutrophil extracellular trap formation pathway, T cell receptor signaling pathway, and nuclear factor-κB signal pathway, were abnormally activated or inhibited in spinal cord injury patient samples. We applied an integrated strategy that combines weighted gene co-expression network analysis, LASSO logistic regression, and SVM-RFE algorithm and identified three biomarkers associated with spinal cord injury: ANO10, BST1, and ZFP36L2. We verified the expression levels and diagnostic performance of these three genes in the original training dataset and clinical samples through the receiver operating characteristic curve. Quantitative polymerase chain reaction results showed that ANO10 and BST1 mRNA levels were increased and ZFP36L2 mRNA was decreased in the peripheral blood of spinal cord injury patients. We also constructed a small RNA-mRNA interaction network using Cytoscape. Additionally, we evaluated the proportion of 22 types of immune cells in the peripheral blood of spinal cord injury patients using the CIBERSORT tool. The proportions of naïve B cells, plasma cells, monocytes, and neutrophils were increased while the proportions of memory B cells, CD8+ T cells, resting natural killer cells, resting dendritic cells, and eosinophils were markedly decreased in spinal cord injury patients increased compared with healthy subjects, and ANO10, BST1 and ZFP26L2 were closely related to the proportion of certain immune cell types. The findings from this study provide new directions for the development of treatment strategies related to immune inflammation in spinal cord injury and suggest that ANO10, BST1, and ZFP36L2 are potential biomarkers for spinal cord injury. The study was registered in the Chinese Clinical Trial Registry (registration No. ChiCTR2200066985, December 12, 2022).
ABSTRACT
Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell activation has been identified as a central mechanism for promoting fibrosis downstream of TGFß. IL11 signaling has recently been reported to promote fibroblast-to-myofibroblast transition, thus leading to various pro-fibrotic phenotypic changes. We confirmed increased mRNA expression of IL11 and IL11Rα in fibrotic diseases by OMICs approaches and in situ hybridization. However, the vital role of IL11 as a driver for fibrosis was not recapitulated. While induction of IL11 secretion was observed downstream of TGFß signaling in human lung fibroblasts and epithelial cells, the cellular responses induced by IL11 was quantitatively and qualitatively inferior to that of TGFß at the transcriptional and translational levels. IL11 blocking antibodies inhibited IL11Rα-proximal STAT3 activation but failed to block TGFß-induced profibrotic signals. In summary, our results challenge the concept of IL11 blockade as a strategy for providing transformative treatment for fibrosis.
Subject(s)
Interleukin-11 , Transforming Growth Factor beta , Humans , Transforming Growth Factor beta/metabolism , Signal Transduction , Fibrosis , Myofibroblasts/metabolismABSTRACT
Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.
Subject(s)
Antibodies , Arthritis, Experimental , Immunoconjugates , Steroids , Humans , Animals , Mice , Pharmaceutical Preparations , Receptors, Glucocorticoid/therapeutic use , Tumor Necrosis Factor Inhibitors/therapeutic use , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Tumor Necrosis Factor-alpha/metabolism , Disease Models, Animal , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic useABSTRACT
Maleimide chemistry is widely used in antibody-drug conjugate (ADC) generation to connect drugs to antibodies through a succinimide linker. The resulting ADC is prone to payload loss via a reverse Michael reaction, leading to premature drug release in vivo. Complete succinimide hydrolysis is an effective strategy to overcome the instability of ADC. However, we discovered through previous work that hydrolysed succinimide rings can close again in a liquid formulation during storage and under thermal stress conditions. In this work, a set of maleimide linkers with hydrolysis-prone groups were designed. The corresponding ADCs were prepared and subjected to thermal stress conditions. The extent of succinimide hydrolysis and drug release was measured, and ADC properties such as SEC, DAR, pI and clog P of linkers were calculated. Our results demonstrated that even though all these groups increased the hydrolysis rate, they have different impacts on maintaining the hydrolysed succinimide ring in an open conformation and ADC stability in a liquid formulation.
ABSTRACT
Leptin is a hormone secreted primarily by adipose tissue. It regulates an organism's metabolism, energy balance, and body weight through a negative feedback mechanism. When a person or animal has low body fat and little energy, the leptin level in the body decreases, and conversely, when there is an excess of nutrients, the leptin level increases, giving a feeling of satiety. However, when leptin levels are abnormal (too high or too low) for a number of reasons, it can negatively affect your health, inducing inflammatory responses, obesity, and other problems. Many studies have shown that abnormal leptin levels, such as hyperleptinemia, are closely associated with common risk factors for atherosclerosis (AS). This review systematically states the relationship between leptin and common risk factors for AS (inflammation, obesity, diabetes mellitus, hypertension, and sleep disorders) and provides some new thoughts on the future direction of research on both. Because the abnormal level of leptin will have adverse effects on multiple atherosclerotic risk factors, how to regulate the leptin level of patients with AS, and whether we can treat and prevent AS by intervening the leptin level, these may be our new research directions in the future.
Subject(s)
Atherosclerosis , Leptin , Animals , Humans , Leptin/metabolism , Obesity/complications , Obesity/epidemiology , Obesity/metabolism , Adipose Tissue/metabolism , Risk Factors , Atherosclerosis/complicationsABSTRACT
Stable attachment of drug-linkers to the antibody is a critical requirement, and for maleimide conjugation to cysteine, it is achieved by ring hydrolysis of the succinimide ring. During ADC profiling in our in-house property screening funnel, we discovered that the succinimide ring open form is in equilibrium with the ring closed succinimide. Bromoacetamide (BrAc) was identified as the optimal replacement, as it affords stable attachment of the drug-linker to the antibody while completely removing the undesired ring open-closed equilibrium. Additionally, BrAc also offers multiple benefits over maleimide, especially with respect to homogeneity of the ADC structure. In combination with a short, hydrophilic linker and phosphate prodrug on the payload, this afforded a stable ADC (ABBV-154) with the desired properties to enable long-term stability to facilitate subcutaneous self-administration.
Subject(s)
Immunoconjugates , Prodrugs , Receptors, Glucocorticoid , Tumor Necrosis Factor Inhibitors , Antibodies , Prodrugs/pharmacology , Glucocorticoids , Maleimides , Immunoconjugates/pharmacologyABSTRACT
KEY MESSAGE: An LRR-RLK gene causing interspecific hybrid breakdown between Gossypium. anomalum and G. hirsutum was identified by deploying a map-based cloning strategy. The self-destructing symptoms of hybrid incompatibility in most cases are attributed to autoimmunity. The cloning of genes responsible for hybrid incompatibility in cotton is helpful to clarify the mechanisms underlying hybrid incompatibility and can break the barriers in distant hybridization. In this study, a temperature-dependent lethality was identified in CSSL11-9 (chromosome segment substitution line) with Gossypium anomalum chromosome segment on chromosome A11. Transcriptome analysis showed the differentially expressed genes related to autoimmune responses were highly enriched, suggesting that expression of CSSL11-9 plant lethal gene activated autoimmunity in the absence of any pathogen or external stimulus, inducing programmed cell death (PCD) and causing a lethal phenotype. The lethal phenotype was controlled by a pair of recessive genes and then fine mapped between JAAS3191-JAAS3050 interval, which covered 63.87 kb in G. hirsutum genome and 98.66 kb in G. anomalum. We demonstrated that an LRR-RLK gene designated as hybrid breakdown 1 (GoanoHBD1) was the causal gene underlying this locus for interspecific hybrid incompatibility between G. anomalum and G. hirsutum. Silencing this LRR-RLK gene could restore CSSL11-9 plants from a lethal to a normal phenotype. Our findings provide new insights into reproductive isolation and may benefit cotton breeding.
Subject(s)
Gossypium , Plant Breeding , Gossypium/genetics , Genes, Recessive , Phenotype , Genes, PlantABSTRACT
OBJECTIVE: Electroacupuncture (EA) has a definite effect on the treatment of spinal cord injuries (SCIs), but its underlying molecular mechanism remains unclear. Meanwhile, MiR106b-5p is an autophagy- and apoptosis-related microribonucleic acid, but whether it regulates the progression of autophagy and apoptosis in SCIs is yet undetermined. As such, this study aimed to elucidate the involvement of miR-106b-5p in the EA treatment of an SCI. METHODS: The miR-106b-5p level was detected by quantitative real-time polymerase chain reaction. In vitro, SH-SY5Y cells were transfected with miR-106b-5p mimics or inhibitors to regulate the miR-106b-5p expression, while in vivo, SCI rats were treated with EA for 7 days at the bilateral Zusanli (ST36) and Jiaji (EX-B2) acupoints. The motor function was evaluated using the Basso-Beattie-Bresnahan (BBB) criteria. Further, autophagic vacuoles, pathological damage, and neuronal cell morphology were observed by transmission electron microscopy, as well as by hematoxylin and eosin and Nissl staining, respectively. RESULTS: The miR-106b-5p level, which can interact directly with Beclin-1 by influencing its expression, as well as the expressions of P62, Caspase-3, and Bax, was upregulated after an SCI, but it decreased after EA. Moreover, the ratio of LC3-II to LC3-I was upregulated after EA. EA can enhance autophagy, reduce neuronal apoptosis, and minimize motor dysfunction and histopathological deficits after an SCI. More importantly, however, all the above effects induced by EA can be reversed after an injection of miR-106-5p agomir to produce an overexpression of miR-106b-5p. CONCLUSION: EA treatment could downregulate miR-106b-5p to alleviate SCI-mediated injuries by promoting autophagy and inhibiting apoptosis.
ABSTRACT
OBJECTIVES: This review aims to assess the efficacy of transcutaneous electrical nerve stimulation (TENS) for neurogenic bladder after spinal cord injury (SCI). MATERIALS AND METHODS: A systematic search was conducted of seven electronic data bases from inception to Dec 31, 2022, to identify randomized controlled trials that studied TENS for neurogenic bladder after SCI. The primary outcomes were maximum cystometric capacity (MCC) and residual urine volume (RUV). Secondary outcomes included maximum detrusor pressure, flow rate, and bladder diary. Random effects models were used in all analyses. RESULTS: Eleven trials involving 881 participants were included. Meta-analysis showed that TENS in addition to conventional treatment had larger MCC (mean difference [MD] 50.55 ml, 95% CI 27.81-73.29, pï¼0.0001) and lower RUV (MD -22.96 ml, 95% CI -33.45 to -12.47, pï¼0.0001) than did conventional treatment only. Compared with magnetic stimulation, no differences were observed with TENS for MCC (MD -14.49 ml, 95% CI -48.97 to 19.98, p = 0.41) and RUV (MD 25 ml, 95% CI -61.79 to 111.79, p = 0.57). There also were no differences in MCC (MD -7.2 ml, 95% CI -14.56 to 0.16, p= 0.06) and (MD -5.2 ml, 95% CI -60.00 to 49.60, p = 0.851) when compared with solifenacin succinate and pelvic floor biofeedback, respectively. CONCLUSIONS: TENS may be an effective treatment option for neurogenic bladder after SCI.
ABSTRACT
To facilitate subcutaneous dosing, biotherapeutics need to exhibit properties that enable high-concentration formulation and long-term stability in the formulation buffer. For antibody-drug conjugates (ADCs), the introduction of drug-linkers can lead to increased hydrophobicity and higher levels of aggregation, which are both detrimental to the properties required for subcutaneous dosing. Herein we show how the physicochemical properties of ADCs could be controlled through the drug-linker chemistry in combination with prodrug chemistry of the payload, and how optimization of these combinations could afford ADCs with significantly improved solution stability. Key to achieving this optimization is the use of an accelerated stress test performed in a minimal formulation buffer.
Subject(s)
Immunoconjugates , Immunoconjugates/chemistry , Hydrophobic and Hydrophilic InteractionsABSTRACT
BACKGROUND: Although transcranial magnetic stimulation (TMS)-based closed-loop (TBCL) modality was seldom recommended for functional restoring following spinal cord injury (SCI), several studies recently came to a positive suggestion. AIM: To explore the independent factors which influence activity of daily living (ADL) gain, and systematically investigate the efficacy of TBCL for ADL gain. DESIGN: A retrospective observational study. SETTING: The First Affiliated Hospital of Guangxi Medical University. POPULATION: SCI patients with neurological dysfunction. METHODS: A total of 768 patients who received TBCL (N.=548) or sole rehabilitation (SR, N.=220) were enrolled. Analysis on propensity score matching was also performed. Finally, the cumulative inefficiencies between TBCL and SR within entire patient population, matched-patients as well as subgroup on per SCI clinical characteristics were performed. RESULTS: Multivariate analysis showed that thoracolumbar injury, single/double injury, incomplete injury, no neurogenic bladder, no neurogenic intestinal and no respiratory disorder, as well as TBCL strategy were independent positive factors for ADL gain. Meanwhile, TBCL strategy was the outstanding positive factor. TBCL caused a lower cumulative inefficiency over SR at 1, 90 and 180 days (83.2% vs. 86.8%, 54.0% vs. 63.6%, and 38.3% vs. 50.9%, respectively; all P<0.05). Propensity matching also found TBCL caused a lower cumulative inefficiency over SR after 1, 90 and 180 days (82.4% vs. 86.4%, 51.1% vs. 62.5%, and 33.5% vs. 49.4%, respectively; all P<0.05). Subgroup analysis showed that TBCL caused a greater ADL gain regardless of injured site, segments of injury and injured extent, as well as whether concurrent with neurogenic bladder, neurogenic intestinal and respiratory disorder (all P<0.05). Further, TBCL was more effective in 180-days overall ADL gain within each subgroup (all P<0.05), except the subgroup whether concurrent with respiratory disorder (P>0.05). CONCLUSIONS: Our study indicates that TBCL strategy was the most outstanding independent positive factors for ADL gain. Further, TBCL is a better choice than SR in ADL gain for SCI-relevant neurological dysfunctions in case of adequate stimuli distance and individual temperature, regardless of discrepancy of clinical feature. CLINICAL REHABILITATION IMPACT: This study helps to improve everyday management for rehabilitative intervention on SCI. For another thing, the present study may be good for neuromodulation practice on function restoring in SCI rehabilitation clinics.
Subject(s)
Spinal Cord Injuries , Urinary Bladder, Neurogenic , Humans , Activities of Daily Living , Retrospective Studies , Transcranial Magnetic Stimulation , Propensity Score , China , Spinal Cord Injuries/rehabilitation , Urinary Bladder, Neurogenic/etiologyABSTRACT
Background: The cardiometabolic index (CMI) has been proposed as a novel indicator of cardiometabolic status. However, evidence on the relationship between CMI and diabetes mellitus (DM) risk was limited. Our study aimed to explore the relationship between CMI and DM risk among a large cohort of Japanese adults. Methods: This retrospective cohort study recruited 15453 Japanese adults without diabetes at baseline who underwent physical examinations at the Murakami Memorial Hospital between 2004 and 2015. Cox proportional-hazards regression was applied to evaluate the independent relationship between CMI and diabetes. Our study performed a generalized smooth curve fitting (penalized spline technique) and an additive model (GAM) to determine the non-linear relationship between CMI and DM risk. In addition, a set of sensitivity analyses and subgroup analyses were employed to evaluate the relationship between CMI and incident DM. Results: After adjusting for confounding covariates, CMI was positively related to the DM risk in Japanese adults (HR: 1.65, 95%CI: 1.43-1.90, P<0.0001). A series of sensitivity analyses were also employed in this study to guarantee the reliability of the findings. In addition, our study discovered a non-linear association between CMI and diabetes risk. CMI's inflection point was 1.01. A strong positive association between CMI and diabetes incidence was also discovered to the left of the inflection point (HR: 2.96, 95%CI: 1.96-4.46, P<<0.0001). However, their association was not significant when CMI was higher than 1.01 (HR: 1.27, 95%CI: 0.98-1.64, P=0.0702). Interaction analysis showed that gender, BMI, habit of exercise, and smoking status interacted with CMI. Conclusion: Increased CMI level at baseline is associated with incident DM. The association between CMI and incident DM is also non-linear. A high CMI level is associated with an increased risk for DM when CMI is below 1.01.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus , Adult , Humans , Cohort Studies , East Asian People , Reproducibility of Results , Retrospective StudiesABSTRACT
Verticillium dahliae is a fungal pathogen that causes Verticillium wilt (VW), which seriously reduces the yield of cotton owing to biological stress. The mechanism underlying the resistance of cotton to VW is highly complex, and the resistance breeding of cotton is consequently limited by the lack of in-depth research. Using quantitative trait loci (QTL) mapping, we previously identified a novel cytochrome P450 (CYP) gene on chromosome D4 of Gossypium barbadense that is associated with resistance to the nondefoliated strain of V. dahliae. In this study, the CYP gene on chromosome D4 was cloned together with its homologous gene on chromosome A4 and were denoted as GbCYP72A1d and GbCYP72A1a, respectively, according to their genomic location and protein subfamily classification. The two GbCYP72A1 genes were induced by V. dahliae and phytohormone treatment, and the findings revealed that the VW resistance of the lines with silenced GbCYP72A1 genes decreased significantly. Transcriptome sequencing and pathway enrichment analyses revealed that the GbCYP72A1 genes primarily affected disease resistance via the plant hormone signal transduction, plant-pathogen interaction, and mitogen-activated protein kinase (MAPK) signaling pathways. Interestingly, the findings revealed that although GbCYP72A1d and GbCYP72A1a had high sequence similarity and both genes enhanced the disease resistance of transgenic Arabidopsis, there was a difference between their disease resistance abilities. Protein structure analysis revealed that this difference was potentially attributed to the presence of a synaptic structure in the GbCYP72A1d protein. Altogether, the findings suggested that the GbCYP72A1 genes play an important role in plant response and resistance to VW.
Subject(s)
Verticillium , Verticillium/physiology , Disease Resistance/genetics , Plant Breeding , Quantitative Trait Loci , Gossypium/genetics , Gossypium/microbiology , Signal TransductionABSTRACT
Heart rate variability (HRV) extracted from the electrocardiogram (ECG) is an essential indicator for assessing the autonomic nervous system in clinical. Some scholars have studied the feasibility of pulse rate variability (PRV) instead of HRV. However, there is little qualitative research in different body states. In this paper, the photoplethysmography (PPG) of postauricular and finger and the ECG of fifteen subjects were synchronously collected for comparative analysis. The eleven experiments were designed according to the daily living state, including the stationary state, limb movement state, and facial movement state. The substitutability of nine variables was investigated in the time, frequency, and nonlinearity domain by Passing Bablok regression and Bland Altman analysis. The results showed that the PPG of the finger was destroyed in the limb movement state. There were six variables of postauricular PRV, which showed a positive linear relationship and good agreement (p > 0.05, ratio ≤0.2) with HRV in all experiments. Our study suggests that the postauricular PPG could retain the necessary information of the pulse signal under the limb movement state and facial movement state. Therefore, postauricular PPG could be a better substitute for HRV, daily PPG detection, and mobile health than finger PPG.
Subject(s)
Electrocardiography , Photoplethysmography , Humans , Heart Rate/physiology , Healthy Volunteers , Photoplethysmography/methods , Electrocardiography/methods , Autonomic Nervous SystemABSTRACT
BACKGROUND: Ischemic stroke (IS) is a serious neurological disease that largely results in long-term disability and death. Extensive evidence has indicated that the activation of inflammation and ferroptosis significantly contribute to the development of IS pathology. However, the underlying molecular mechanism remains unclear. In this study, we aimed to identify potential biomarkers associated with IS through the construction of a competing endogenous RNA (ceRNA) network and to investigate the possible inflammatory and ferroptosis-related molecular mechanisms. RESULTS: We identified 178 differentially expressed target messenger RNAs (DETmRNAs) associated with IS. As revealed through enrichment analysis, the DEmRNAs were mainly enriched in the inflammatory signaling pathways and also related to ferroptosis mechanism. The CIBERSORT algorithm showed immune infiltration landscapes in which the naïve B cells, naïve T cells, and monocytes had statistically different numbers in the cerebral infarction group compared with the control group. A ceRNA network was constructed in this study involving 44 long non-coding RNAs (lncRNAs), 15 microRNAs (miRNAs), and 160 messenger RNAs (mRNAs). We used the receiver operating characteristic (ROC) analysis to identify three miRNAs (miR-103a-3p, miR-140-3p, and miR-17-5p), one mRNA (TLR4), and one lncRNA (NEAT1) as the potential key biomarkers of the ceRNA network. The key mRNA and lncRNA were shown to be highly related to the ferroptosis mechanism of IS. The expression of these key biomarkers was also further validated by a method of quantitative real-time polymerase chain reaction in SH-SY5Y cells, and the validated results were consistent with the findings predicted by bioinformatics. CONCLUSION: Our results suggest that the ceRNA network may exert an important role in the inflammatory and ferroptosis molecular mechanisms of IS, providing new insight into therapeutic IS targets.
Subject(s)
Ischemic Stroke , MicroRNAs , Neuroblastoma , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , Ischemic Stroke/genetics , Gene Regulatory Networks , Biomarkers, Tumor/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
BACKGROUND: In recent years, non-invasive brain stimulation (NIBS) has been used for motor function recovery. However, the effects of NIBS in populations with spinal cord injury (SCI) remain unclear. This study aims to conduct a meta-analysis of the existing evidence on the effects and safety of NIBS against sham groups for motor dysfunction after SCI to provide a reference for clinical decision-making. METHODS: Two investigators systematically screened English articles from PubMed, MEDLINE, Embase, and Cochrane Library for prospective randomized controlled trials regarding the effects of NIBS in motor function recovery after SCI. Studies with at least three sessions of NIBS were included. We assessed the methodological quality of the selected studies using the evidence-based Cochrane Collaboration's tool. A meta-analysis was performed by pooling the standardized mean difference (SMD) with 95% confidence intervals (CI). RESULTS: A total of 14 randomized control trials involving 225 participants were included. Nine studies used repetitive transcranial magnetic stimulation (rTMS) and five studies used transcranial direct current stimulation (tDCS). The meta-analysis showed that NIBS could improve the lower extremity strength (SMD = 0.58, 95% CI = 0.02-1.14, P = 0.004), balance (SMD = 0.64, 95% CI = 0.05-1.24, P = 0.03), and decrease the spasticity (SMD = - 0.64, 95% CI = - 1.20 to - 0.03, P = 0.04). However, the motor ability of the upper extremity in the NIBS groups was not statistically significant compared with those in the control groups (upper-extremity strength: P = 0.97; function: P = 0.56; and spasticity: P = 0.12). The functional mobility in the NIBS groups did not reach statistical significance when compared with the sham NIBS groups (sham groups). Only one patient reported seizures that occurred during stimulation, and no other types of serious adverse events were reported. CONCLUSION: NIBS appears to positively affect the motor function of the lower extremities in SCI patients, despite the marginal P-value and the high heterogeneity. Further high-quality clinical trials are needed to support or refute the use and optimize the stimulation parameters of NIBS in clinical practice.
Subject(s)
Spinal Cord Injuries , Transcranial Direct Current Stimulation , Humans , Prospective Studies , Transcranial Magnetic Stimulation , Spinal Cord Injuries/therapy , Muscle Spasticity/etiology , Muscle Spasticity/therapy , Brain/physiology , Randomized Controlled Trials as TopicABSTRACT
Over the past decade, therapeutic monoclonal antibodies (mAbs) have established their role as valuable agents in the treatment of various diseases ranging from cancers to infectious, cardiovascular and autoimmune diseases. Reactive groups of the amino acids within these proteins make them susceptible to many kinds of chemical modifications during manufacturing, storage and in vivo circulation. Among these reactions, the oxidation of methionine residues to their sulfoxide form is a commonly observed chemical modification in mAbs. When the oxidized methionine is in the complementarity-determining region (CDR), this modification can affect antigen binding and thus abrogate biological activity. For these reasons, it is essential to identify oxidation liabilities during the antibody discovery and development phases. Here, we present an in silico method, based on protein modeling and molecular dynamics simulations, to predict the oxidation-liable residues in the variable region of therapeutic antibodies. Previous studies have used the 2-shell water coordination number descriptor (WCN) to identify methionine residues susceptible to oxidation. Although the WCN descriptor successfully predicted oxidation liabilities when the residue was solvent exposed, the method was much less accurate for partially buried methionine residues. Consequently, we introduce a new descriptor, WCN-OH, that improves the accuracy of prediction of methionine oxidation susceptibility by extending the theoretical framework of the water coordination number to incorporate the effects of polar amino acids side chains in close proximity to the methionine of interest.