ABSTRACT
Vibration is an indispensable part of the tactile perception, which is encoded to oscillatory synaptic currents by receptors and transferred to neurons in the brain. The A2 and B1 neurons in the drosophila brain postsynaptic to the vibration receptors exhibit selective preferences for oscillatory synaptic currents with different frequencies, which is caused by the specific voltage-gated Na+ and K+ currents that both oppose the variations in membrane potential. To understand the peculiar role of the Na+ and K+ currents in shaping the filtering property of A2 and B1 neurons, we develop a linearized modeling framework that allows to systematically change the activation properties of these ionic channels. A data-driven conductance-based biophysical model is used to reproduce the frequency filtering of oscillatory synaptic inputs. Then, this data-driven model is linearized at the resting potential and its frequency response is calculated based on the transfer function, which is described by the magnitude-frequency curve. When we regulate the activation properties of the Na+ and K+ channels by changing the biophysical parameters, the dominant pole of the transfer function is found to be highly correlated with the fluctuation of the active current, which represents the strength of suppression of slow voltage variation. Meanwhile, the dominant pole also shapes the magnitude-frequency curve and further qualitatively determines the filtering property of the model. The transfer function provides a parsimonious description of how the biophysical parameters in Na+ and K+ channels change the inhibition of slow variations in membrane potential by Na+ and K+ currents, and further illustrates the relationship between the filtering properties and the activation properties of Na+ and K+ channels. This computational framework with the data-driven conductance-based biophysical model and its linearized model contributes to understanding the transmission and filtering of vibration stimulus in the tactile system.
ABSTRACT
The mechanisms of anxiety disorders, the most common mental illness, remain incompletely characterized. The ventral hippocampus (vHPC) is critical for the expression of anxiety. However, current studies primarily focus on vHPC neurons, leaving the role for vHPC astrocytes in anxiety largely unexplored. Here, genetically encoded Ca2+ indicator GCaMP6m and in vivo fiber photometry calcium imaging are used to label vHPC astrocytes and monitor their activity, respectively, genetic and chemogenetic approaches to inhibit and activate vHPC astrocytes, respectively, patch-clamp recordings to measure glutamate currents, and behavioral assays to assess anxiety-like behaviors. It is found that vHPC astrocytic activity is increased in anxiogenic environments and by 3-d subacute restraint stress (SRS), a well-validated mouse model of anxiety disorders. Genetic inhibition of vHPC astrocytes exerts anxiolytic effects on both innate and SRS-induced anxiety-related behaviors, whereas hM3Dq-mediated chemogenetic or SRS-induced activation of vHPC astrocytes enhances anxiety-like behaviors, which are reversed by intra-vHPC application of the ionotropic glutamate N-methyl-d-aspartate receptor antagonists. Furthermore, intra-vHPC or systemic application of the N-methyl-d-aspartate receptor antagonist memantine, a U.S. FDA-approved drug for Alzheimer's disease, fully rescues SRS-induced anxiety-like behaviors. The findings highlight vHPC astrocytes as critical regulators of stress and anxiety and as potential therapeutic targets for anxiety and anxiety-related disorders.
ABSTRACT
Objective: To preliminarily explore the risk factors for post-infectious bronchiolitis obliterans (PIBO) complicating adenovirus pneumonia (ADVP) in children through a meta-analysis. Methods: A systematic search was conducted on three English-language databases (PubMed, Web of Science and The National Library of Medicine) and two Chinese-language databases (China National Knowledge Infrastructure and the Wanfang Database) between database inception and 1 January 2023. Data analysis was conducted using Stata 15.1 software. Results: A total of 10 articles, reporting 14 risk factors, were included in the analysis, with 8 risk factors taken into consideration. Through the meta-analysis, 5 risk factors were identified for PIBO complicating ADVP in paediatric patients: hypoxaemia [odds ratio (OR) = 9.37, 95% CI: 4.22, 20.77, p < 0.001], persistent wheezing (OR = 4.65, 95% CI: 2.20, 9.82, p < 0.001), mechanical ventilation (OR = 3.87, 95% CI: 2.37, 6.33, p < 0.001), length of hospital stay (LoHS) (OR = 1.25, 95% CI: 1.09, 1.43, p < 0.001) and fever duration (OR = 1.08, 95% CI: 1.02, 1.14, p = 0.009). Conclusion: Existing evidence suggests that hypoxaemia, persistent wheezing, mechanical ventilation, LoHS and fever duration are risk factors for PIBO complicating ADVP in children. These findings underscore the need for enhanced assessment and management in clinical practice. This study may provide such a clinical prediction model from the identified 5 risk factors for PIBO and offer valuable insights for preventing bronchiolitis obliterans in children with ADVP.
ABSTRACT
Background: Erythrocyte dysfunction is a characteristic of diabetes mellitus (DM). However, erythrocyte-associated biomarkers do not adequately explain the high prevalence of DM. Here, we describe red blood cell distribution width to albumin ratio (RAR) as a novel inflammatory biomarker for evaluating an association with DM prevalence and prognosis of all-cause mortality. Methods: Data analyzed in this study were extracted from the National Health and Nutrition Examination Survey (NHANES) 1999-2020. A total of 40,558 participants (non-DM and DM) were enrolled in the study; RAR quartiles were calibrated at Q1 [2.02,2.82] mL/g, Q2 (2.82,3.05] mL/g, Q3 (3.05,3.38] mL/g, and Q4 (3.38,12.08] mL/g. A total of 8,482 DM patients were followed (for a median of 84 months), of whom 2,411 died and 6,071 survived. The prevalence and prognosis associated with RAR and DM were analyzed; age and sex were stratified to analyze the prevalence of RAR in DM and the sensitivity of long-term prognosis. Results: Among non-DM (n=30,404) and DM (n=10,154) volunteers, DM prevalence in RAR quartiles was 8.23%, 15.20%, 23.92%, and 36.39%. The multivariable odds ratio (OR) was significant for RAR regarding DM, at 1.68 (95% CI 1.42, 1.98). Considering Q1 as a foundation, the Q4 OR was 2.57 (95% CI 2.11, 3.13). The percentages of DM morbidity varied across RAR quartiles for dead (n=2,411) and surviving (n=6,071) DM patients. Specifically, RAR quartile mortality ratios were 20.31%, 24.24%, 22.65%, and 29.99% (P<0.0001). The multivariable hazard ratio (HR) for RAR was 1.80 (95% CI 1.57, 2.05). Considering Q1 as a foundation, the Q4 HR was 2.59 (95% CI 2.18, 3.09) after adjusting for confounding factors. Sensitivity analysis revealed the HR of male DM patients to be 2.27 (95% CI 1.95, 2.64), higher than females 1.56 (95% CI 1.31, 1.85). DM patients who were 60 years of age or younger had a higher HR of 2.08 (95% CI1.61, 2.70) as compared to those older than 60 years, who had an HR of 1.69 (95% CI 1.47, 1.94). The HR of RAR in DM patients was optimized by a restricted cubic spline (RCS) model; 3.22 was determined to be the inflection point of an inverse L-curve. DM patients with a RAR >3.22 mL/g suffered shorter survival and higher mortality as compared to those with RAR ≤3.22 mL/g. OR and HR RAR values were much higher than those of regular red blood cell distribution width. Conclusions: The predictive value of RAR is more accurate than that of RDW for projecting DM prevalence, while RAR, a DM risk factor, has long-term prognostic power for the condition. Survival time was found to be reduced as RAR increased for those aged ≤60 years among female DM patients.
Subject(s)
Diabetes Mellitus , Erythrocyte Indices , Nutrition Surveys , Humans , Male , Female , Prognosis , Middle Aged , Prevalence , Diabetes Mellitus/epidemiology , Diabetes Mellitus/blood , Adult , Aged , Biomarkers/blood , Erythrocytes/metabolism , Serum Albumin/analysis , Serum Albumin/metabolismABSTRACT
BACKGROUND AND AIM: Inflammatory diseases often result in bone loss due to persistent inflammation, which activates osteoclasts and increases bone resorption. Oxysophocarpine (OSC), a bioalkaloid extracted from the roots of Sophora japonica and other leguminous plants, has neuroprotective and anti-tumor properties. However, it is still uncertain whether OSC can effectively inhibit the differentiation of osteoclasts and bone resorption. Therefore, this study explored the potential role of OSC in osteoclast formation and inflammatory osteolysis and its underlying mechanisms. EXPERIMENTAL PROCEDURE: This study involved inducing primary mouse bone marrow macrophages (BMMs) into osteoclasts using macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) and examined the effects of OSC on osteoclast (OC) differentiation, function, and intracellular reactive oxygen species (ROS) production. The impact of OSC on the expression of osteoclast-specific genes and inflammation-related factors was assessed using real-time quantitative PCR. Additionally, changes in oxidative stress-related factors, NF-κB, and MAPK signaling pathways were examined using western blotting. Finally, this study investigated the influence of OSC on a mouse cranial bone resorption model induced by titanium (Ti) particles in vivo. RESULTS: OSC inhibited OC differentiation and resorption and reduces intracellular ROS levels. Moreover, OSC suppressed IL-1ß, TNF-α, IL-6, and osteoclast-specific gene transcription while increasing Nrf2 and HO-1 protein expression. Furthermore, OSC inhibited the expression and autoregulation of the NFATc1 gene, ultimately leading to a reduction in Ti particle-induced bone resorption in mice. CONCLUSION: OSC could be regarded as an innovative medication for the treatment of osteoclast-associated inflammatory osteolytic diseases.
ABSTRACT
Introduction: Reward and punishment modulate behavior. In real-world motor skill learning, reward and punishment have been found to have dissociable effects on optimizing motor skill learning, but the scientific basis for these effects is largely unknown. Methods: In the present study, we investigated the effects of reward and punishment on the performance of real-world motor skill learning. Specifically, three groups of participants were trained and tested on a ping-pong ball bouncing task for three consecutive days. The training and testing sessions were identical across the three days: participants were trained with their right (dominant) hand each day under conditions of either reward, punishment, or a neutral control condition (neither). Before and after the training session, all participants were tested with their right and left hands without any feedback. Results: We found that punishment promoted early learning, while reward promoted late learning. Reward facilitated short-term memory, while punishment impaired long-term memory. Both reward and punishment interfered with long-term memory gains. Interestingly, the effects of reward and punishment transferred to the left hand. Discussion: The results show that reward and punishment have different effects on real-world motor skill learning. The effects change with training and transfer readily to novel contexts. The results suggest that reward and punishment may act on different learning processes and engage different neural mechanisms during real-world motor skill learning. In addition, high-level metacognitive processes may be enabled by the additional reinforcement feedback during real-world motor skill learning. Our findings provide new insights into the mechanisms underlying motor learning, and may have important implications for practical applications such as sports training and motor rehabilitation.
ABSTRACT
Metabolomics has been used extensively to identify crucial molecules and biochemical effects induced by environmental factors. To understand the effects of acute low-salinity stress on Fenneropenaeus chinensis, intestinal histological examination and untargeted metabonomic analysis of F. chinensis were performed after exposure to a salinity of 15 ppt for 3, 7, and 14 d. The histological examination revealed that acute stress resulted in most epithelial cells rupturing, leading to the dispersion of nuclei in the intestinal lumen after 14 days. Metabolomics analysis identified numerous differentially expressed metabolites (DEMs) at different time points after exposure to low-salinity stress, in which some DEMs were steadily downregulated at the early stage of stress and then gradually upregulated. We further screened 14 overlapping DEMs, in which other DEMs decreased significantly during low-salinity stress, apart from L-palmitoylcarnitine and vitamin A, with enrichments in phenylalanine, tyrosine and tryptophan biosynthesis, fatty acid and retinol metabolism, and ABC transporters. ABC transporters exhibit significant abnormalities and play a vital role in low-salinity stress. This study provides valuable insights into the molecular mechanisms underlying the responses of F. chinensis to acute salinity stress.
ABSTRACT
Mule duck is vitally important to the production of global duck meat. Here, we present two high-quality haplotypes of a female mule duck (haplotype 1 (H1):1.28 Gb, haplotype 2 (H2): 1.40 Gb). The continuity (H1: contig N50 = 14.90 Mb, H2: contig N50 = 15.70 Mb) and completeness (BUSCO: H1 = 96.9%, H2 = 97.3%) are substantially better than those of other duck genomes. We detected the structural variations (SVs) in H1 and H2. We observed a positive correlation between autosome length and the number of SVs. Z chromosome was some deficient in deletions and insertions, but W chromosome was some excessive. A total of 1,451 genes were haplotype specific expression (HSEs). Among them, 737 specifically expressed in H1, and 714 specifically expressed in H2. We found that H1 and H2 HSEs tended to be involved in similar biological processes, such as myometrial relaxation and contraction pathways, muscle structure development and phosphorylation. Our haplotype-resolved genome assembly provides a powerful platform for future functional genomics, molecular breeding, and genome editing in mule duck.
Subject(s)
Ducks , Genome , Haplotypes , Animals , Ducks/genetics , Female , High-Throughput Nucleotide Sequencing/methodsABSTRACT
Morphing materials are typically either very compliant to achieve large shape changes or very stiff but with small shape changes that require large actuation forces. Interestingly, fish fins overcome these limitations: fish fins do not contain muscles, yet they can change the shape of their fins with high precision and speed while producing large hydrodynamic forces without collapsing. Here, we present a 'stiff' morphing beam inspired from the individual rays in natural fish fins. These synthetic rays are made of acrylic (PMMA) outer beams ('hemitrichs') connected with rubber ligaments which are 3-4 orders of magnitude more compliant. Combinations of experiments and models of these synthetic rays show strong nonlinear geometrical effects: the ligaments are 'mechanically invisible' at small deformations, but they delay buckling and improve the stability of the ray at large deformations. We use the models and experiments to explore designs with variable ligament densities, and we generate design guidelines for optimum morphing shape (captured using the first moment of curvature), that capture the trade-offs between morphing compliance (ease of morphing the structure) and flexural stiffness. The design guidelines proposed here can help the development of stiff morphing bioinspired structures for a variety of applications in aerospace, biomedicine or robotics.
ABSTRACT
The rapid development of the mariculture industry has been hindered by limited coastal aquaculture space. To utilize the abundant inland saline-alkaline water, we studied the physiological effects of high carbonate alkalinity stress and high pH stress on Fenneropenaeus chinensis. The study employed quantitative proteomics by tandem mass tag (TMT) and non-targeted metabolomics analysis using a liquid chromatograph mass spectrometer (LC-MS) to understand the physiological and biochemical adaptive mechanisms of the hepatopancreas of F. chinensis in response to saline-alkaline stress at the molecular level. We designed two stress groups as follows: a high carbonate alkalinity (CA) group and a combined high carbonate alkalinity and high pH (CP) group. The study found that the protein and metabolic profiles of the two stress groups were changed, and the CP group, which was exposed to dual stresses, incurred more severe damage to the hepatopancreas compared to that of the CA group. After exposure to CA and CP, the hepatopancreas of F. chinensis showed significant alterations in 455 proteins and 50 metabolites, and 1988 proteins and 272 metabolites, respectively. In addition, F. chinensis upregulated the level of energy metabolism in the hepatopancreas to defend against osmotic imbalance caused by CA or CP stress, which was demonstrated by the significant upregulation of important proteins and metabolites in glycolysis, pyruvate metabolism, TCA cycle, and fatty acid oxidation. Additionally, pattern recognition receptors, the phenol oxidase system, and various immune-related metabolic enzymes and metabolites were also affected. The immune homeostasis of F. chinensis was affected by the alteration of the antioxidant system following exposure to CA or CP. These findings provide valuable information for F. chinensis saline-alkaline water cultivation practices.
ABSTRACT
Pregabalin is a medication primarily used in the treatment of neuropathic pain and anxiety disorders, owing to its gabapentinoid properties. Pregabalin monotherapy faces limitations due to its variable efficacy and dose-dependent adverse reactions. In this study, we conducted a comprehensive investigation into the potentiation of pregabalin's analgesic effects by dexborneol, a neuroprotective bicyclic monoterpenoid compound. We performed animal experiments where pain models were induced using two methods: peripheral nerve injury, involving axotomy and ligation of the tibial and common peroneal nerves, and incisional pain through a longitudinal incision in the hind paw, while employing a multifaceted methodology that integrates behavioral pharmacology, molecular biology, neuromorphology, and lipidomics to delve into the mechanisms behind this potentiation. Dexborneol was found to enhance pregabalin's efficacy by promoting its transportation to the central nervous system, disrupting self-amplifying vicious cycles via the reduction of HMGB1 and ATP release, and exerting significant anti-oxidative effects through modulation of central lipid metabolism. This combination therapy not only boosted pregabalin's analgesic property but also notably decreased its side effects. Moreover, this therapeutic cocktail exceeded basic pain relief, effectively reducing neuroinflammation and glial cell activation-key factors contributing to persistent and chronic pain. This study paves the way for more tolerable and effective analgesic options, highlighting the potential of dexborneol as an adjuvant to pregabalin therapy.
ABSTRACT
AIMS AND OBJECTIVES: The main aim of this study is to synthesize the prevalent predictive models for pressure injuries in hospitalized patients, with the goal of identifying common predictive factors linked to pressure injuries in hospitalized patients. This endeavour holds the potential to provide clinical nurses with a valuable reference for providing targeted care to high-risk patients. BACKGROUND: Pressure injuries (PIs) are a frequently occurring health problem throughout the world. There are mounting studies about risk prediction model of PIs reported and published. However, the prediction performance of the models is still unclear. DESIGN: Systematic review and meta-analysis: The Cochrane Library, PubMed, Embase, CINAHL, Web of Science and Chinese databases including CNKI (China National Knowledge Infrastructure), Wanfang Database, Weipu Database and CBM (China Biology Medicine). METHODS: This systematic review was conducted following PRISMA recommendations. The databases of Cochrane Library, PubMed, Embase, CINAHL, Web of Science, and CNKI, Weipu Database, Wanfang Database and CBM were searched for all studies published before September 2023. We included studies with cohort, case-control designs, reporting the development of risk model and have been validated externally and internally among the hospitalized patients. Two researchers selected the retrieved studies according to the inclusion and exclusion criteria, and critically evaluated the quality of studies based on the CHARMS checklist. The PRISMA guideline was used to report the systematic review and meta-analysis. RESULTS: Sixty-two studies were included, which contained 99 pressure injuries risk prediction models. The AUC (area under ROC curve) of modelling in 32 prediction models were reported ranged from .70 to .99, while the AUC of verification in 38 models were reported ranged from .70 to .98. Gender (OR = 1.41, CI: .99 ~ 1.31), age (WMD = 8.81, CI: 8.11 ~ 9.57), diabetes mellitus (OR = 1.64, CI: 1.36 ~ 1.99), mechanical ventilation (OR = 2.71, CI: 2.05 ~ 3.57), length of hospital stay (WMD = 7.65, CI: 7.24 ~ 8.05) were the most common predictors of pressure injuries. CONCLUSION: Studies of PIs risk prediction model in hospitalized patients had high research quality, and the risk prediction models also had good predictive performance. However, some of the included studies lacked of internal or external validation in modelling, which affected the stability and extendibility. The aged, male patient in ICU, albumin, haematocrit, low haemoglobin level, diabetes, mechanical ventilation and length of stay in hospital were high-risk factors for pressure injuries in hospitalized patients. In the future, it is recommended that clinical nurses, in practice, select predictive models with better performance to identify high-risk patients based on the actual situation and provide care targeting the high-risk factors to prevent the occurrence of diseases. RELEVANCE TO CLINICAL PRACTICE: The risk prediction model is an effective tool for identifying patients at the risk of developing PIs. With the help of risk prediction tool, nurses can identify the high-risk patients and common predictive factors, predict the probability of developing PIs, then provide specific preventive measures to improve the outcomes of these patients. REGISTRATION NUMBER (PROSPERO): CRD42023445258.
ABSTRACT
Sulfadiazine (SDZ) is frequently detected in environmental samples, arousing much concern due to its toxicity and hard degradation. This study investigated the electricity generation capabilities, SDZ removal and microbial communities of a highly efficient mixed-culture system using repeated transfer enrichments in a bio-electrochemical system. The mixed-culture biofilm (S160-T2) produced a remarkable current density of 954.12 ± 15.08 µA cm-2 with 160 mg/L SDZ, which was 32.9 and 1.8 times higher than that of Geobacter sulfurreducens PCA with 40 mg/L SDZ and without additional SDZ, respectively. Especially, the impressive SDZ removal rate of 98.76 ± 0.79% was achieved within 96 h using the further acclimatized mixed-culture. The removal efficiency of this mixed-culture for SDZ through the bio-electrochemical system was 1.1 times higher than that using simple anaerobic biodegradation. Furthermore, the current density and removal efficiency in this system gradually decreased with increasing SDZ concentrations from 0 to 800 mg/L. In addition, community diversity data demonstrated that the dominant genera, Geobacter and Escherichia-Shigella, were enriched in mixed-culture biofilm, which might be responsible for the current production and SDZ removal. This work confirmed the important roles of acclimatized microbial consortia and co-substrates in the simultaneous removal of SDZ and electricity generation in an electrochemical system.
Subject(s)
Bioelectric Energy Sources , Biofilms , Geobacter , Sulfadiazine , Geobacter/metabolism , Geobacter/physiology , Geobacter/isolation & purification , Bioelectric Energy Sources/microbiology , Electricity , Biosensing Techniques , Biodegradation, Environmental , Electrochemical Techniques/methodsABSTRACT
BACKGROUND: Dose-response and nonlinear relationships of cigarette exposure with sleep disturbances and depression are warranted, and the potential mechanism of sex hormones in such associations remains unclear. METHODS: Cigarette exposure, trouble sleeping, and depression were assessed by standard questionnaires, and the levels of cotinine and sex steroid hormones were determined among 9900 adults from the National Health and Nutrition Examination Survey (NHANES). Multiple linear regression, logistic regression, and mediation models were conducted to evaluate the associations between smoking, sex steroid hormones, trouble sleeping, and depression. RESULTS: With never smokers as a reference, current smokers had a higher prevalence of trouble sleeping (OR = 1.931, 95% CI: 1.680, 2.219) and depression (OR = 2.525, 95% CI: 1.936, 3.293) as well as testosterone level (ß = 0.083, 95% CI: 0.028, 0.140). Pack-years of smoking and cigarettes per day were positively associated with the prevalence of trouble sleeping and depression as well as testosterone level (Ptrend <0.05). The restricted cubic spline model showed linear relationships of cotinine with trouble sleeping, depression, and testosterone. The positive associations of cigarettes per day with trouble sleeping and depression were greater in females than that in males (Pmodification <0.05). However, the potential role of sex hormones was not observed in the association of cotinine with trouble sleeping or depression (Pmediation >0.05). CONCLUSION: Smoking may induce sex hormone disturbance and increase the risk of sleep problems and depression symptoms, and ceasing smoking may reduce the risk of such complications.
Subject(s)
Cotinine , Depression , Nutrition Surveys , Humans , Male , Female , Cross-Sectional Studies , Adult , Depression/epidemiology , Middle Aged , United States/epidemiology , Cotinine/blood , Cotinine/analysis , Sleep Wake Disorders/epidemiology , Smoking/epidemiology , Prevalence , Gonadal Steroid Hormones/blood , Young Adult , Testosterone/blood , AgedABSTRACT
BACKGROUND: Multiple genetic and epigenetic regulatory mechanisms are crucial in the development and tumorigenesis process. Transcriptional regulation often involves intricate relationships and networks with post-transcriptional regulatory molecules, impacting the spatial and temporal expression of genes. However, the synergistic relationship between transcription factors and N6-methyladenosine (m6A) modification in regulating gene expression, as well as their influence on the mechanisms underlying the occurrence and progression of non-small cell lung cancer (NSCLC), requires further investigation. The present study aimed to investigate the synergistic relationship between transcription factors and m6A modification on NSCLC. METHODS: The transcription factor NFIC and its potential genes was screened by analyzing publicly available datasets (ATAC-seq, DNase-seq, and RNA-seq). The association of NFIC and its potential target genes were validated through ChIP-qPCR and dual-luciferase reporter assays. Additionally, the roles of NFIC and its potential genes in NSCLC were detected in vitro and in vivo through silencing and overexpression assays. RESULTS: Based on multi-omics data, the transcription factor NFIC was identified as a potential tumor suppressor of NSCLC. NFIC was significantly downregulated in both NSCLC tissues and cells, and when NFIC was overexpressed, the malignant phenotype and total m6A content of NSCLC cells was suppressed, while the PI3K/AKT pathway was inactivated. Additionally, we discovered that NFIC inhibits the expression of METTL3 by directly binding to its promoter region, and METTL3 regulates the expression of KAT2A, a histone acetyltransferase, by methylating the m6A site in the 3'UTR of KAT2A mRNA in NSCLC cells. Intriguingly, NFIC was also found to negatively regulate the expression of KAT2A by directly binding to its promoter region. CONCLUSIONS: Our findings demonstrated that NFIC suppresses the malignant phenotype of NSCLC cells by regulating gene expression at both the transcriptional and post-transcriptional levels. A deeper comprehension of the genetic and epigenetic regulatory mechanisms in tumorigenesis would be beneficial for the development of personalized treatment strategies.
ABSTRACT
Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PL-mediodorsal thalamic nucleus (MD) projection, and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggests that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders.
Subject(s)
Anxiety , Neural Pathways , Prefrontal Cortex , Stress, Psychological , Animals , Anxiety/psychology , Anxiety/physiopathology , Male , Stress, Psychological/psychology , Stress, Psychological/physiopathology , Prefrontal Cortex/physiopathology , Neural Pathways/physiopathology , Neural Pathways/physiology , Mice , Fear/physiology , Fear/psychology , Mice, Inbred C57BL , Ventral Tegmental Area/physiopathology , Thalamus/physiopathology , Mediodorsal Thalamic Nucleus/physiology , Mediodorsal Thalamic Nucleus/physiopathologyABSTRACT
The Ebola virus (EBOV) is a lethal pathogen causing hemorrhagic fever syndrome which remains a global health challenge. In the EBOV, two multifunctional proteins, VP35 and VP40, have significant roles in replication, virion assembly, and budding from the cell and have been identified as druggable targets. In this study, we employed in silico methods comprising molecular docking, molecular dynamic simulations, and pharmacological properties to identify prospective drugs for inhibiting VP35 and VP40 proteins from the myxobacterial bioactive natural product repertoire. Cystobactamid 934-2, Cystobactamid 919-1, and Cittilin A bound firmly to VP35. Meanwhile, 2-Hydroxysorangiadenosine, Enhypyrazinone B, and Sorangiadenosine showed strong binding to the matrix protein VP40. Molecular dynamic simulations revealed that, among these compounds, Cystobactamid 919-1 and 2-Hydroxysorangiadenosine had stable interactions with their respective targets. Similarly, molecular mechanics Poisson-Boltzmann surface area (MMPBSA) calculations indicated close-fitting receptor binding with VP35 or VP40. These two compounds also exhibited good pharmacological properties. In conclusion, we identified Cystobactamid 919-1 and 2-Hydroxysorangiadenosine as potential ligands for EBOV that target VP35 and VP40 proteins. These findings signify an essential step in vitro and in vivo to validate their potential for EBOV inhibition.
Subject(s)
Antiviral Agents , Biological Products , Ebolavirus , Molecular Docking Simulation , Molecular Dynamics Simulation , Ebolavirus/drug effects , Biological Products/pharmacology , Biological Products/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Myxococcales/chemistry , Humans , Viral Regulatory and Accessory Proteins/antagonists & inhibitors , Viral Regulatory and Accessory Proteins/metabolism , Viral Regulatory and Accessory Proteins/chemistry , Viral Matrix Proteins/antagonists & inhibitors , Viral Matrix Proteins/metabolism , Viral Matrix Proteins/chemistry , Nucleocapsid ProteinsABSTRACT
OBJECTIVE: To compare the effectiveness and safety of nab-paclitaxel, cisplatin, and capecitabine (nab-TPC) with gemcitabine and cisplatin as an alternative first line treatment option for recurrent or metastatic nasopharyngeal carcinoma. DESIGN: Phase 3, open label, multicentre, randomised trial. SETTING: Four hospitals located in China between September 2019 and August 2022. PARTICIPANTS: Adults (≥18 years) with recurrent or metastatic nasopharyngeal carcinoma. INTERVENTIONS: Patients were randomised in a 1:1 ratio to treatment with either nab-paclitaxel (200 g/m2 on day 1), cisplatin (60 mg/m2 on day 1), and capecitabine (1000 mg/m2 twice on days 1-14) or gemcitabine (1 g/m2 on days 1 and 8) and cisplatin (80 mg/m2 on day 1). MAIN OUTCOME MEASURES: Progression-free survival was evaluated by the independent review committee as the primary endpoint in the intention-to-treat population. RESULTS: The median follow-up was 15.8 months in the prespecified interim analysis (31 October 2022). As assessed by the independent review committee, the median progression-free survival was 11.3 (95% confidence interval 9.7 to 12.9) months in the nab-TPC cohort compared with 7.7 (6.5 to 9.0) months in the gemcitabine and cisplatin cohort. The hazard ratio was 0.43 (95% confidence interval 0.25 to 0.73; P=0.002). The objective response rate in the nab-TPC cohort was 83% (34/41) versus 63% (25/40) in the gemcitabine and cisplatin cohort (P=0.05), and the duration of response was 10.8 months in the nab-TPC cohort compared with 6.9 months in the gemcitabine and cisplatin cohort (P=0.009). Treatment related grade 3 or 4 adverse events, including leukopenia (4/41 (10%) v 13/40 (33%); P=0.02), neutropenia (6/41 (15%) v 16/40 (40%); P=0.01), and anaemia (1/41 (2%) v 8/40 (20%); P=0.01), were higher in the gemcitabine and cisplatin cohort than in the nab-TPC cohort. No deaths related to treatment occurred in either treatment group. Survival and long term toxicity are still being evaluated with longer follow-up. CONCLUSION: The nab-TPC regimen showed a superior antitumoural efficacy and favourable safety profile compared with gemcitabine and cisplatin for recurrent or metastatic nasopharyngeal carcinoma. Nab-TPC should be considered the standard first line treatment for recurrent or metastatic nasopharyngeal carcinoma. Longer follow-up is needed to confirm the benefits for overall survival. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900027112.
Subject(s)
Albumins , Antineoplastic Combined Chemotherapy Protocols , Capecitabine , Cisplatin , Deoxycytidine , Gemcitabine , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Neoplasm Recurrence, Local , Paclitaxel , Humans , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Cisplatin/adverse effects , Male , Middle Aged , Female , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/mortality , Deoxycytidine/analogs & derivatives , Deoxycytidine/administration & dosage , Deoxycytidine/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Capecitabine/therapeutic use , Capecitabine/administration & dosage , Adult , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/mortality , Neoplasm Recurrence, Local/drug therapy , Paclitaxel/administration & dosage , Paclitaxel/therapeutic use , Paclitaxel/adverse effects , Albumins/administration & dosage , Albumins/adverse effects , Albumins/therapeutic use , Aged , Progression-Free Survival , China , Neoplasm MetastasisABSTRACT
Visible particle is an important issue in the biopharmaceutical industry, and it may occur across all the stages in the life cycle of biologics. Upon the occurrence of visible particles, it is often necessary to conduct chemical identification and root cause analysis to safeguard the safety and efficacy of the biotherapeutic products. In this article, we present a number of typical particles and relevant root cause analysis in the categories of extrinsic, intrinsic and inherent particles that are commonly encountered in the biopharma industry. In particular, the optical images of particles obtained both in situ and after isolation are provided, along with the spectral and elemental information. The particle identification was carried out with multiple microscopic and microspectroscopic techniques, including stereo optical microscopy, Fourier transform infrared microscopy, confocal Raman microscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy. Both commercial and in-house spectral databases were used for comparison and identification. In addition to particle identification, our significant efforts are placed on the root cause analysis of the addressed particles with the intention to provide a relatively whole picture of the particle related issues and practical references to particle mitigation for our peers in the biopharmaceutical industry.