RESUMO

BACKGROUND: The recent Maternal Immune Activation (MIA) theory suggests maternal systemic inflammation may serve as a mediator in associations between prenatal maternal adversities and neurodevelopmental diseases in offspring. Given the co-exposure to multiple adversities may be experienced by pregnant person, it is unclear whether a quantitative index can be developed to characterize the inflammation related exposure level, and whether this index is associated with neurodevelopmental delays in offspring. METHODS: Based on Jiangsu Birth Cohort (JBC), a total of 3051 infants were included in the analysis. Inflammation related Prenatal Adversity Index (IPAI) was constructed using maternal data. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development, third edition, screening test in one year. Multivariate linear regression and Poisson regression model were performed to analyze the associations between IPAI and neurodevelopment in offspring. RESULTS: Compared with "low IPAI" group, offspring with "high IPAI" have lower scores of cognition, receptive communication, expressive communication, and fine motor. The adjusted ß were - 0.23 (95%CI: -0.42, -0.04), -0.47 (95%CI: -0.66, -0.28), -0.30 (95%CI: -0.49, -0.11), and - 0.20 (95%CI: -0.33, -0.06). Additionally, the elevated risk for noncompetent development of cognition and receptive communication among "high IPAI" group was observed. The relative risk [RR] and 95% confidence interval [CI] were 1.35 (1.01, 1.69) and 1.37 (1.09, 1.72). CONCLUSIONS: Our results revealed a significant association between higher IPAI and lower scores across cognition, receptive communication, expressive communication, and fine motor domains, and an increased risk of noncompetent development in the cognition and receptive communication domains.

Assuntos

Coorte de Nascimento , Inflamação , Transtornos do Neurodesenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Humanos , Feminino , Gravidez , Estudos Prospectivos , Estudos Longitudinais , Masculino , Lactente , Adulto , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/epidemiologia , Desenvolvimento Infantil , China/epidemiologia

RESUMO

Dengue virus (DENV) gains genetic mutations during continuous transmission and evolution, making the virus more adaptive and virulent. The clade of DENV-1 genotype I has expanded and become the predominant genotype in Asia and the Pacific areas, but the underlying mechanisms are unclear. A combined analysis of nonsynonymous mutations in domain III of the envelope protein and their biological effects on virus pathogenesis and transmission was evaluated. Phylogenetic analyses found three nonsynonymous mutations (V324I, V351L, and V380I) in domain III of the envelope protein, which emerged in 1970s-1990s and stably inherited and expanded in contemporary strains after 2000. We generated reverse-mutated viruses (I324V, L351V, and I380V) based on an infectious clone of an epidemic DENV-1 strain (NIID02-20), and the results suggested that the infectivity of the contemporary epidemic virus (wild type, WT) has increased compared to the reverse mutant viruses in mammalian hosts but not mosquito vectors. The WT virus showed a higher binding affinity to host cells and increased virion stability. In addition, weaker immunogenicity and higher resistance to neutralizing antibodies of the WT virus indicated a trend of immune escape. The data suggested that nonsynonymous mutations of the E protein (V324I, V351L, and V380I) promote infectivity and immune evasion of DENV-1 genotype I, which may facilitate its onward transmission on a global scale. IMPORTANCE: We provide evidence that minor sequence variation among dengue virus (DENV) strains can result in increased adaptability and virulence, impacting both the biology of the virus and the antiviral immune response. The genetic mutations of DENV-1 gained during continuous transmission and evolution will offer new clues for the design of novel vaccines against flaviviruses.

RESUMO

Dynamic gain control of aversive signals enables adaptive behavioral responses. Although the role of amygdalar circuits in aversive processing is well established, the neural pathway for amplifying aversion remains elusive. Here, we show that the brainstem circuit linking the interpeduncular nucleus (IPN) with the nucleus incertus (NI) amplifies aversion and promotes avoidant behaviors. IPN GABA neurons are activated by aversive stimuli and their predicting cues, with their response intensity closely tracking aversive values. Activating these neurons does not trigger aversive behavior on its own but rather amplifies responses to aversive stimuli, whereas their ablation or inhibition suppresses such responses. Detailed circuit dissection revealed anatomically distinct subgroups within the IPN GABA neuron population, highlighting the NI-projecting subgroup as the modulator of aversiveness related to fear and opioid withdrawal. These findings unveil the IPN-NI circuit as an aversion amplifier and suggest potential targets for interventions against affective disorders and opioid relapse.

RESUMO

SUMMARY: Mobile genetic elements (MEs) are heritable mutagens that significantly contribute to genetic diseases. The advent of long-read sequencing technologies, capable of resolving large DNA fragments, offers promising prospects for the comprehensive detection of ME variants (MEVs). However, achieving high precision while maintaining recall performance remains challenging mainly brought by the variable length and similar content of MEV signatures, which are often obscured by the noise in long reads. Here, we propose MEHunter, a high-performance MEV detection approach utilizing a fine-tuned transformer model adept at identifying potential MEVs with fragmented features. Benchmark experiments on both simulated and real datasets demonstrate that MEHunter consistently achieves higher accuracy and sensitivity than the state-of-the-art tools. Furthermore, it is capable of detecting novel potentially individual-specific MEVs that have been overlooked in published population projects. AVAILABILITY AND IMPLEMENTATION: MEHunter is available from https://github.com/120L021101/MEHunter.

Assuntos

Análise de Sequência de DNA , Software , Análise de Sequência de DNA/métodos , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequências Repetitivas Dispersas , Algoritmos

RESUMO

OBJECTIVE: Obesity is one of the most prominent health issues in modern society. Although previous research has identified chronic psychological stress as a risk factor for obesity, much of this research only examined how an individual's own stress affects their adiposity. The current study utilized an actor-partner interdependence model to examine the unique associations of youths' and parents' chronic stress with both their own and each other's adiposity. METHOD: Five hundred sixty-nine dyads of youths (48.7% females, 49.9% Whites, Mage = 13.70 years) and one of their parents (82.6% females, 58.2% Whites, Mage = 45.38 years) participated in a cross-sectional lab study, where both youths and parents completed interviews and anthropometric measurements. Trained interviewers conducted the UCLA Life Stress Interview to assess chronic psychological stress of youths and parents, respectively. Youth and parent adiposity was measured using three indicators, including body mass index, waist circumference, and body fat percentage. RESULTS: The actor-partner interdependence model showed that when both youths' and parents' chronic stress were included simultaneously in the model, youths' chronic stress was uniquely associated with both their own and their parents' adiposity, and parents' chronic stress was also uniquely associated with youths' adiposity. CONCLUSION: Chronic psychological stress of youths and parents is uniquely associated with each other's adiposity, over and above their own stress. Thus, the psychosocial experiences of close others can be linked to both youth and adult obesity. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

RESUMO

Aberrant activation of the innate immune molecule STING can initiate inflammation and autoimmune diseases. Small molecule inhibitors targeting STING have demonstrated therapeutic efficacy against these conditions. Moreover, employing degradants to target STING represents a novel approach to drug design strategy. Consequently, we have designed and synthesized a series of covalent degradants targeting STING. Among them, compound P8 exhibited the highest degradation capacity, with a 24-h DC50 of 2.58 µM in THP-1 cells. In THP-1 cells, P8 specifically degraded STING proteins through the lysosomal pathway, acting as dual a degrader and inhibitor to manifest anti-inflammatory effects. Conversely, in RAW264.7 cells, P8 solely acted as an inhibitor without exhibiting degradative capacity towards the STING protein level. Additionally, P8 displayed renal-protective properties in a cisplatin-induced acute kidney injury model. These results highlight the significant potential of further investigating compound P8.

RESUMO

Ulcerative colitis (UC) is a typical inflammatory bowel disease (IBD), impairing the quality of life of patients. Dehydroevodiamine (DHE) is an active alkaloid isolated from Tetradium ruticarpum that exerts significant anti-inflammatory effects in gastrointestinal diseases. However, the effect and mechanisms of DHE on UC remain unclear. We performed a DSS-induced experimental UC rat model to reveal the efficacy and potential mechanisms of DHE on UC. HE and AB-PAS staining were used for the evaluation of pathologies, and 16S rRNA sequencing was used to detect changes in gut microbes. Metabolomics was used to detect changes in serum metabolites. Network pharmacology and transcriptomics were conducted to reveal the underlying mechanisms of DHE for UC. HuProt proteome microarrays, molecular docking, and SPR were used to reveal the targets of action of DHE. WB, RT-qPCR, and IHC were used to assess the action effects of DHE. DHE demonstrated significant alleviation of DSS-induced colitis symptoms in rats by suppressing inflammatory and oxidative stress responses, amending colonic barrier injury, and inhibiting apoptosis. In terms of gut microbial modulation, DHE decreased the abundance of Allobaculum, Clostridium, Escherichia, Enterococcus, and Barnesiella and increased the abundance of Lactobacillus, Bifidobacterium, and SMB5. Moreover, metabolomics suggested that the regulation of DHE in DSS-induced UC rats mainly involved aminoacyl-tRNA biosynthesis, vitamin B6 metabolism, phenylalanine, tyrosine, and so on. Mechanically, DHE alleviated UC in rats by targeting AKT1, thereby inhibiting the PI3K/AKT/NF-κB signaling pathway.

Assuntos

Alcaloides , Colite Ulcerativa , Microbioma Gastrointestinal , Transdução de Sinais , Animais , Masculino , Ratos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/microbiologia , Sulfato de Dextrana , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Alcaloides/administração & dosagem

RESUMO

Elbow stiffness can severely affect a patient's quality of life. If conservative treatment is ineffective, surgical treatment including open or arthroscopic release could be applied. With the advantages of being minimally invasive, reducing pain and scars, accelerating early rehabilitation, and so on, arthroscopic release has increased in popularity compared with open surgery over the years, whereas limiting factors such as the close proximity of the neurovasculature to the working field and narrow working space still have to be faced by the elbow arthroscopist, with an increasing risk of iatrogenic injury with portal creation and operations adjacent to the nerves and vessels. When elbow arthritis occurs concomitantly with cubital tunnel syndrome, osteophytes on the medial ridge of the olecranon and trochlea occur as obstacles to the elbow extending or the posterior bundle of the medial collateral ligament has to be released for extension contractures, and open procedures for the medial gutter are routinely performed. To reduce the risk of injury and produce even less scar tissue, we present a surgical technique applicable to posteromedial elbow pathology by 2 medial portals. Through this technique, the entire course of the ulnar nerve is exposed and released under arthroscopy, with the ulnar nerve retracted medially, and medial gutter osteophytectomy and soft-tissue release can freely proceed.

RESUMO

Objective: This study evaluated the expression of TIM-3 and its influence on macrophage polarisation in recalcitrant chronic rhinosinusitis with nasal polyps (CRSwNP). Methods: We detected TIM-3 expression in serum and tissue samples of healthy controls (HC), primary CRSwNP, and patients with recurrent CRSwNP. Macrophage markers were detected among three groups, and their correlations with TIM-3 levels were examined. Macrophages from circulating blood were collected and used to examine the impact of TIM-3 on polarisation in vitro. Results: TIM-3 levels were enhanced in the CRSwNP group compared to the HC group. Tissue immunofluorescence revealed elevated TIM-3 expression in patients with CRSwNP, and patients with multiple recurrences exhibited higher TIM-3 levels compared to their first recurrence and baseline levels. Tissue CD163 and CD206 levels were higher in recurrent CRSwNP in comparison with primary cases and HCs, and had a positive correlation with TIM-3 levels. TIM-3 overexpression promoted M2 polarisation and enhanced TGF-ß1 and IL-10 secretion. Conclusions: TIM-3 expression was enhanced in patients with CRSwNP, especially in those undergoing revision surgeries. TIM-3 may be a novel biomarker for recalcitrant CRSwNP. TIM-3-driven M2 polarisation might be involved in the mechanisms of recurrent CRSwNP.

Assuntos

Receptor Celular 2 do Vírus da Hepatite A , Macrófagos , Pólipos Nasais , Rinite , Sinusite , Humanos , Sinusite/imunologia , Sinusite/metabolismo , Sinusite/complicações , Pólipos Nasais/imunologia , Pólipos Nasais/complicações , Pólipos Nasais/metabolismo , Rinite/imunologia , Rinite/metabolismo , Rinite/complicações , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Doença Crônica , Masculino , Feminino , Macrófagos/metabolismo , Pessoa de Meia-Idade , Adulto , Rinossinusite

RESUMO

AIMS: This study explores the plant growth-promoting effect (PGPE) and potential mechanisms of the arsenic (As)-resistant bacterium Flavobacterium sp. A9 (A9 hereafter). METHODS AND RESULTS: The influences of A9 on the growth of Arabidopsis thaliana, lettuce, and Brassica napus under As(V) stress were investigated. Additionally, a metabolome analysis was conducted to unravel the underlying mechanisms that facilitate PGPE. Results revealed that A9 significantly enhanced the fresh weight of Arabidopsis seedlings by 62.6%-135.4% under As(V) stress. A9 significantly increased root length (19.4%), phosphorus (25.28%), chlorophyll content (59%), pod number (24.42%), and weight (18.88%), while decreasing As content (48.33%, P ≤ .05) and oxidative stress of Arabidopsis. It also significantly promoted the growth of lettuce and B. napus under As(V) stress. A9 demonstrated the capability to produce ≥31 beneficial substances contributing to plant growth promotion (e.g. gibberellic acid), stress tolerance (e.g. thiamine), and reduced As accumulation (e.g. siderophores). CONCLUSIONS: A9 significantly promoted the plant growth under As stress and decreased As accumulation by decreasing oxidative stress and releasing beneficial compounds.

Assuntos

Arabidopsis , Arsênio , Brassica napus , Flavobacterium , Estresse Oxidativo , Arsênio/metabolismo , Brassica napus/crescimento & desenvolvimento , Brassica napus/microbiologia , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/microbiologia , Arabidopsis/efeitos dos fármacos , Flavobacterium/crescimento & desenvolvimento , Flavobacterium/efeitos dos fármacos , Lactuca/microbiologia , Lactuca/crescimento & desenvolvimento , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/microbiologia , Clorofila/metabolismo , Plântula/crescimento & desenvolvimento , Plântula/microbiologia , Estresse Fisiológico , Microbiologia do Solo , Giberelinas/metabolismo , Giberelinas/farmacologia , Sideróforos/metabolismo , Desenvolvimento Vegetal/efeitos dos fármacos , Farmacorresistência Bacteriana

RESUMO

Pelvic fracture is a serious injury, which has a profound impact on sexual function due to concurrent nervous and urethral injuries. In this case report, we describe a 29-year-old single man who had retrograde ejaculation as a result of a pelvic fracture-related posterior urethral stricture. The patient wanted to improve his ejaculatory ability after experiencing urethral stricture for 8 years and retrograde ejaculation for 3 years following the pelvic fracture. We precisely located and measured the patient's urethral stricture using a retrograde urethrogram, and we used transrectal color Doppler ultrasound to track the patient's ejaculation process in real time. Next, we used urethral balloon dilatation to relieve the urethral stricture. Urinary obstruction symptoms have completely resolved, and the patient was able to urinate without any obstructions. Meanwhile, the real-time transrectal color Doppler ultrasound result showed that some semen might ejaculate externally by passing through the initial stricture area, while some semen continued to flow retrogradely into the bladder.

Assuntos

Ejaculação , Estreitamento Uretral , Humanos , Masculino , Adulto , Ultrassonografia Doppler em Cores , Fraturas Ósseas/complicações , Fraturas Ósseas/diagnóstico por imagem , Ossos Pélvicos/lesões , Ossos Pélvicos/diagnóstico por imagem , Ejaculação Retrógrada

RESUMO

Degradable polymers are an effective solution for white plastic pollution. Polycaprolactone is a type of degradable plastic with desirable mechanical and biocompatible properties, and its monomer, ε-caprolactone (ε-CL), is often synthesized by Baeyer-Villiger (B-V) oxidation that demands peroxyacids with low safety and low atom-efficiency. Herein, we devised an electrochemical B-V oxidation system simply driven by H2O2 for the efficient production of ε-CL. This system involves two steps with the direct oxidation of H2O2 into •OOH radicals at the electrode surface and the indirect oxidation of cyclohexanone by the generated reactive oxygen species. The modulation of the interfacial ionic environment by amphipathic sulfonimide anions [e.g., bis(trifluoromethane)sulfonimide (TFSI-)] is highly critical. It enables the efficient B-V oxidation into ε-caprolactone with ∼100% selectivity and 68.4% yield at a potential of 1.28 V vs RHE, much lower than the potentials applied for electrochemical B-V oxidation systems using water as the O sources. On hydrophilic electrodes with the action of sulfonimide anions, hydrophilic H2O2 can be enriched within the double layer for direct oxidation while hydrophobic cyclohexanone can be simultaneously accumulated for rapidly reacting with the reactive oxygen species. This work not only enriches the electrified method of the ancient B-V oxidation by using only H2O2 toward monomer production of biodegradable plastics but also emphasizes the critical role of the interfacial ionic environment for electrosynthesis systems that may extend the scope of activity optimization.

RESUMO

Nanopore sequence technology has demonstrated a longer read length and enabled to potentially address the limitations of short-read sequencing including long-range haplotype phasing and accurate variant calling. However, there is still room for improvement in terms of the performance of single nucleotide variant (SNV) identification and computing resource usage for the state-of-the-art approaches. In this work, we introduce miniSNV, a lightweight SNV calling algorithm that simultaneously achieves high performance and yield. miniSNV utilizes known common variants in populations as variation backgrounds and leverages read pileup, read-based phasing, and consensus generation to identify and genotype SNVs for Oxford Nanopore Technologies (ONT) long reads. Benchmarks on real and simulated ONT data under various error profiles demonstrate that miniSNV has superior sensitivity and comparable accuracy on SNV detection and runs faster with outstanding scalability and lower memory than most state-of-the-art variant callers. miniSNV is available from https://github.com/CuiMiao-HIT/miniSNV.

Assuntos

Algoritmos , Sequenciamento por Nanoporos , Polimorfismo de Nucleotídeo Único , Sequenciamento por Nanoporos/métodos , Software , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos

RESUMO

Perovskite multiple quantum wells (MQWs) have shown great potential in the field of light-emitting diodes (LEDs). However, the random formation of QWs with varying well widths (n numbers) often leads to suboptimal interface defects and charge transport issues. Here, we reveal that the crystallization sequence of bromide-based perovskite MQWs is large-n QWs preceding small-n QWs. With this insight, we prevent the crystallization of subsequent small-n QWs by reducing the crystallization rate, ultimately resulting in the crystallization of only n = 5 QWs. This reduction in the crystallization rate is achieved through the chemical interaction of dual additives with perovskite constituents. Additionally, the chemical interaction effectively passivates the uncoordinated lead ions defects. Consequently, pure-phase perovskite QWs with a high photoluminescence quantum efficiency of 75% are achieved. The resulting green LEDs achieve a peak external quantum efficiency of 17.1% and a maximum luminance of 29,480 cd m-2, which is attractive for full-color display applications of perovskites.

RESUMO

BACKGROUND: Research on immunotherapy for gastric cancer is currently receiving significant attention, with particular emphasis on the role of CD8+ T cells in anti-tumor immune responses. In recent years, the importance of the chemokine CXCL10 in promoting anti-tumor immunity has been increasingly recognized because it plays a crucial role in recruiting CD8+ T cells to the tumor microenvironment. The Huang-Jin-Shuang-Shen (HJSS) Decoction, a Chinese medicine, has been used as an adjuvant drug for gastric cancer chemotherapy. Its mechanism of action may be related to the activation of anti-tumor immunity. PURPOSE: To assess the role of the HJSS Decoction in regulating the immune microenvironment of gastric cancer and elucidate its mechanism. STUDY DESIGN/METHODS: Ultra-high performance liquid chromatography Q Exactive-mass spectrometry was used to analyze the main components of the HJSS Decoction and evaluate the therapeutic effect of the HJSS Decoction synergized with 5-fluorouracil (5-FU) on gastric cancer. The proportions of CD8+ T cells and killing markers were determined using flow cytometry. Mechanisms of action and targets were screened using network pharmacology. The level of CXCL10 was detected using enzyme-linked immunosorbent assay and western blot, and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) related signaling pathway was detected in vitro. The target function was validated by siRNA transfection. RESULTS: The combination of HJSS Decoction and 5-FU demonstrated a synergistic effect in impeding the progression of subcutaneous gastric cancer. This was achieved through the facilitation of apoptosis and suppression of proliferation. Furthermore, HJSS Decoction exhibited the ability to enhance the population of CD8+ T cells and augment their cytotoxic capabilities, both in laboratory settings and in living organisms. Notably, HJSS Decoction upregulated the expression of CXCL10, and mechanistically, it activated the NFκB-related signaling pathway to initiate subsequent transcription of chemokines. CONCLUSION: The present study aimed to investigate the pharmacological mechanism of the HJSS Decoction and its potential clinical application in inhibiting gastric cancer in mice. HJSS Decoction can cooperate with 5-FU to inhibit gastric cancer, and the optimal dose is medium. HJSS Decoction exerts anti-tumor immunity by activating the NFκB-related signaling pathway and promoting the expression of CXCL10, which in turn recruits CD8+ T cells into the tumor immune microenvironment. Overall, these findings provide valuable evidence for the potential clinical application of HJSS Decoction.

RESUMO

BACKGROUND: Cholestasis (CT) is a group of disorders caused by impaired production, secretion or excretion of bile. This may result in the deposition of bile components in the blood and liver, which in turn causes damage to liver cells and other tissues. If untreated, CT can progress to severe complications, including cirrhosis, liver failure, and potentially life-threatening conditions. OBJECTIVE: This research was intended to elucidate the function and mechanism of Paeoniflorin (PF) in ameliorating ANIT-induced pyroptosis in CT. METHODS: CT models were established in SD rats and HepG2 cells through ANIT treatment. Histological examination was conducted using haematoxylin and eosin (HE) staining to assess the histopathological alterations in the liver. Network pharmacology was employed to identify potential PF targets in CT treatment. To evaluate pyroptosis levels, various methods were used, including serum biochemical analysis, Enzyme-Linked Immunosorbent Assay (ELISA), immunofluorescence (IF), immunohistochemistry (IHC), Western blotting, transmission electron microscopy (TEM), and scanning electron microscopy (SEM). The HuProt™ 20K Chip was utilized to pinpoint potential PF-binding targets. PF's direct mechanisms in CT treatment were explored using molecular docking (MD), molecular dynamics simulations (MDS), Cellular Thermal Shift Assay (CETSA), and Surface Plasmon Resonance (SPR). RESULTS: PF administration was found to alleviate ANIT-induced liver pathology, enhance liver function markers, and improve cell viability. Network pharmacology and pyroptosis inhibitor studies suggested that PF might mitigate CT via the NLRP3-dependent pyroptosis pathway. This hypothesis was further supported by Western blotting, IF, and IHC analyses, which indicated PF's potential to inhibit NLRP3-dependent pyroptosis in CT. GSDMD was identified as a target through HuProt™ 20K Chip screening. The binding affinity of PF to GSDMD was validated through MD, MDS, CETSA, and SPR techniques. Additionally, the regulatory impact of GSDMD on downstream inflammatory pathways was confirmed by ELISA and IHC. CONCLUSION: PF exhibited a hepatoprotective effect in ANIT-induced CT, primarily by targeting GSDMD, thereby suppressing ANIT-induced pyroptosis and the subsequent release of inflammatory mediators.

Assuntos

Colestase , Glucosídeos , Monoterpenos , Proteínas de Ligação a Fosfato , Piroptose , Ratos Sprague-Dawley , Transdução de Sinais , Piroptose/efeitos dos fármacos , Animais , Glucosídeos/farmacologia , Monoterpenos/farmacologia , Humanos , Transdução de Sinais/efeitos dos fármacos , Masculino , Ratos , Células Hep G2 , Colestase/tratamento farmacológico , Colestase/induzido quimicamente , Proteínas de Ligação a Fosfato/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Simulação de Acoplamento Molecular , Modelos Animais de Doenças , Farmacologia em Rede , Gasderminas

RESUMO

Epigenetic regulation plays a central role in the regulation of a number of cellular processes such as proliferation, differentiation, cell cycle, and apoptosis. In particular, small molecule epigenetic modulators are key elements that can effectively influence gene expression by precisely regulating the epigenetic state of cells. To identify useful small-molecule regulators that enhance the expression of recombinant proteins in Chinese hamster ovary (CHO) cells, we examined a novel dual-HDAC/LSD1 inhibitor I-4 as a supplement for recombinant CHO cells. Treatment with 2 µM I-4 was most effective in increasing monoclonal antibody production. Despite cell cycle arrest at the G1/G0 phase, which inhibits cell growth, the addition of the inhibitor at 2 µM to monoclonal antibody-expressing CHO cell cultures resulted in a 1.94-fold increase in the maximal monoclonal antibody titer and a 2.43-fold increase in specific monoclonal antibody production. In addition, I-4 significantly increased the messenger RNA levels of the monoclonal antibody and histone H3 acetylation and methylation levels. We also investigated the effect on HDAC-related isoforms and found that interference with the HDAC5 gene increased the monoclonal antibody titer by 1.64-fold. The results of this work provide an effective method of using epigenetic regulatory strategies to enhance the expression of recombinant proteins in CHO cells. KEY POINTS: • HDAC/LSD1 dual-target small molecule inhibitor can increase the expression level of recombinant monoclonal antibodies in CHO cells. • By affecting the acetylation and methylation levels of histones in CHO cells and downregulating HDAC5, the production of recombinant monoclonal antibodies increased. • It provides an effective pathway for applying epigenetic regulation strategies to enhance the expression of recombinant proteins.

Assuntos

Anticorpos Monoclonais , Cricetulus , Epigênese Genética , Proteínas Recombinantes , Células CHO , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/farmacologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histonas/metabolismo , Histonas/genética , Acetilação , Cricetinae , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Metilação

RESUMO

Purpose: Our study aims to evaluate differences in muscle parameters of the quadriceps muscles in patients with knee osteoarthritis (KOA) in older adults. Methods: The study included 40 patients diagnosed with unilateral knee osteoarthritis in the KOA group (KG) and 40 asymptomatic elderly individuals in the control group (CG). Muscle ultrasonic mean echo intensity and shear modulus, as well as tone and stiffness of the rectus femoris (RF), vastus medialis (VM), and vastus lateralis (VL) were analyzed. Additionally, clinical correlations were performed. Results: In the KG group, there were significant differences in echo intensity, shear modulus, and tone between the affected and unaffected sides for RF (p=0.003, 0.019, 0.014), while VM showed significant differences in shear modulus and tone (p=0.006, 0.002). Additionally, VL exhibited significant differences in echo intensity, shear modulus, and stiffness (p=0.007, 0.006, 0.010). Compared to the CG group, the KG group showed significant differences in echo intensity of the affected side RF (p=0.001). VM exhibited statistically significant differences in echo intensity and shear modulus (p < 0.001, p=0.008), while VL showed statistically significant differences in echo intensity, tone, and stiffness (p < 0.001, p=0.028, p < 0.001). The correlation results showed that patients with unilateral KOA, VM, and VL echo intensity were correlated with K-L grade (r = 0.443, p=0.004; r = 0.469, p=0.002). The tone of VL was correlated with VAS and WOMAC (r = 0.327, p=0.039; r = 0.344, p=0.030). Conclusion: The parameters of the quadriceps femoris muscle exhibit asymmetry between the affected and unaffected sides in patients with unilateral KOA, as well as a difference between the dominant side of healthy older individuals and the affected side of KOA.

Assuntos

Osteoartrite do Joelho , Músculo Quadríceps , Ultrassonografia , Humanos , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/fisiopatologia , Músculo Quadríceps/diagnóstico por imagem , Músculo Quadríceps/fisiopatologia , Masculino , Feminino , Idoso , Fenômenos Biomecânicos , Pessoa de Meia-Idade , Estudos de Casos e Controles

RESUMO

Global increases in the intensity and frequency of wildfires are driving major changes in soil organic matter (SOM) characteristics, including soil dissolved organic matter (DOM). As the most crucial component of SOM, soil DOM plays a pivotal role in the carbon cycle and regulates the environmental fate of contaminants through its versatile reactivities, including electron-donating capacity (EDC). However, it is still being determined how wildfire influences key characteristics of soil DOM and subsequent effects on EDC in forest soils. Thus, we conducted our study to fill this gap with the forest soils of Jinyun Mountain Nature Reserve of China, which experienced an unprecedented wildfire event in 2022. The results from optical characterization, high-performance size-exclusion chromatography (HPSEC), and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) showed decreasing molecular weight but elevating nitrogen-containing molecular formulas of soil DOM in the burned soils. This could be attributed to the Maillard reaction and microbial re-colonies. Additionally, wildfires increased the condensed aromatics and lignin components in soil DOM. In the burned soils, we observed increasing EDC of soil DOM, which accounts for an increase in lignin-derived phenolic components. Overall, the findings of this study demonstrate that eco-disturbances, such as wildfires, induce alterations in the properties of DOM, leading to variations in its reactivity and potentially influencing the fate of environmental pollutants beyond carbon dynamics alone. Thus, incorporating the dynamic properties of soil DOM, particularly in the context of climate change, can enhance the assessment of risks associated with contaminants in soil and water, providing valuable insights.

RESUMO

The sluggish kinetics of hydrogen evolution reaction (HER) via water reduction limits the efficiency of alkaline water electrolysis. The HER kinetics is not only intimately related to the catalyst surface structure but also relevant to the cation identity of the electrolyte. The cation dependence also relies on the surface electronic structure and applied potential, but this interrelated effect and its underlying mechanism awaits elucidation. Herein, differently-charged molybdenum sulfide (MoSx) cluster supports ([Mo3S13]2- and [Mo3S7]4+) are utilized to hybridize with the identical metallic Ru centers. The specific electrostatic interaction between MoSx clusters and Ru precursors induces different Ru valences of the hybrids, with a higher valence state for Ru/Mo3S13 endowing a higher activity. The Ru/Mo3S13 and Ru/Mo3S7 exhibited drastically-different cation dependence, in which the charged support determines the local accumulation of cations and resulting water structures. The more negatively-charged Mo3S13 support induces the facile accumulation of cations, especially for less-hydrated K+ cations. The water activation capability by Ru valences and cation accumulation from the support effect in-together determine the cation-dependent alkaline HER activity. This work not only enriches the understanding about the cation-dependent HER mechanism but also shines a light on the rational optimization strategy of electrode/electrolyte interfaces.